CN111182904A

CN111182904A - Combination therapy comprising ACC inhibitors

Info

Publication number: CN111182904A
Application number: CN201880064837.9A
Authority: CN
Inventors: J.G.贝茨; A.S.雷
Original assignee: Gilead Sciences Inc
Current assignee: Gilead Sciences Inc
Priority date: 2017-10-06
Filing date: 2018-10-05
Publication date: 2020-05-19
Also published as: TWI814744B; KR20200060476A; AU2021273669A1; US20210308136A1; US11963961B2; EP3691648A1; TW201924687A; KR102419458B1; JP7479278B2; US20190134041A1; JP2022169806A; CA3077273A1; US10980810B2; AU2018345817A1; WO2019071216A1; JP2020536866A; AU2018345817B2; KR20220103807A

Abstract

The present invention provides methods and compositions for treating, stabilizing or reducing the severity or progression of non-alcoholic fatty liver disease.

Description

Combination therapy comprising ACC inhibitors

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional application No. 62/569,375 filed 2017, 10, 6, 2017, U.S. provisional application No. 62/593,806 filed 2017, 12, 1, and U.S. provisional application No. 62/655,704 filed 2018, 4, 10, 35, which are incorporated herein by reference in their entirety.

Technical Field

Provided herein are pharmaceutical combinations and methods of treating, stabilizing or reducing the severity or progression of non-alcoholic fatty liver disease (NAFLD).

Background

Nonalcoholic fatty liver disease (NAFLD) includes a range of conditions, from relatively benign steatosis to more severe nonalcoholic steatohepatitis (NASH), which, if untreated, can lead to fibrosis, cirrhosis, liver failure, or hepatocellular carcinoma. NAFLD is the most common cause of chronic liver disease in the united states and is closely associated with obesity, type 2 diabetes and metabolic syndrome.

Disclosure of Invention

in some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of non-alcoholic fatty liver disease comprising administering to a patient in need thereof a combination of an acetyl-CoA carboxylase (ACC) inhibitor and a peroxisome proliferator-activated receptor alpha (PPAR α) agonist or fish oil.

In some aspects, the ACC inhibitor is (R) -2- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) -2-methylpropionic acid having the formula:

or a pharmaceutically acceptable salt, solvate or co-crystal thereof (collectively and individually referred to as "compound 1").

In some aspects, the ACC inhibitor is 2- [1- [ (2R) -2- [ (4-hydroxycyclohexyl) oxy ] -2- (2-methoxyphenyl) ethyl ] -5-methyl-6- (1, 3-oxazol-2-yl) -2, 4-dioxo-1H, 2H,3H, 4H-thieno [2,3-d ] pyrimidin-3-yl ] -2-methylpropionic acid having the formula:

or a pharmaceutically acceptable salt, solvate or co-crystal thereof (collectively and individually referred to as "compound 2").

in some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of non-alcoholic fatty liver disease while reducing or eliminating the appearance of or reducing the severity of hypertriglyceridemia, wherein the method comprises administering to a patient in need thereof an ACC inhibitor in combination with a PPAR α agonist or fish oil.

in some aspects, provided herein are methods of treating, stabilizing or reducing the severity or progression of nonalcoholic steatohepatitis, wherein the method comprises administering to a patient in need thereof an ACC inhibitor in combination with a PPAR α agonist or fish oil.

in some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of non-alcoholic steatohepatitis while reducing or eliminating the appearance of or reducing the severity of hypertriglyceridemia, wherein the method comprises administering to a patient in need thereof an ACC inhibitor in combination with a PPAR α agonist or fish oil.

in some aspects, provided herein is a method of treating, stabilizing, or reducing the severity or progression of non-alcoholic fatty liver disease while reducing or eliminating the appearance of or reducing the severity of hypertriglyceridemia, wherein the method comprises administering compound 1 in combination with a PPAR α agonist or fish oil to a patient in need thereof.

in some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of non-alcoholic steatohepatitis, wherein the method comprises administering compound 1 in combination with a PPAR α agonist or fish oil to a patient in need thereof.

in some aspects, provided herein is a method of treating, stabilizing, or reducing the severity or progression of non-alcoholic steatohepatitis while reducing or eliminating the appearance of or reducing the severity of hypertriglyceridemia, wherein the method comprises administering compound 1 in combination with a PPAR α agonist or fish oil to a patient in need thereof.

in some aspects, provided herein is a method of treating, stabilizing, or reducing the severity or progression of non-alcoholic fatty liver disease while reducing or eliminating the appearance of or reducing the severity of hypertriglyceridemia, wherein the method comprises administering compound 2 in combination with a PPAR α agonist or fish oil to a patient in need thereof.

in some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of non-alcoholic steatohepatitis, wherein the method comprises administering compound 2 in combination with a PPAR α agonist or fish oil to a patient in need thereof.

in some aspects, provided herein is a method of treating, stabilizing, or reducing the severity or progression of non-alcoholic steatohepatitis while reducing or eliminating the appearance of or reducing the severity of hypertriglyceridemia, wherein the method comprises administering compound 2 in combination with a PPAR α agonist or fish oil to a patient in need thereof.

in some aspects, the invention provides a pharmaceutical composition comprising compound 1 or compound 2 and a PPAR α agonist, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

In some aspects, provided herein is a method of treating non-alcoholic steatohepatitis in a non-cirrhosis patient with non-alcoholic steatohepatitis, wherein the method comprises administering to a patient in need thereof once daily about 20mg of compound 1.

In some aspects, provided herein is a method of treating nonalcoholic steatohepatitis (NASH) in a patient having compensated cirrhosis due to NASH, wherein the method comprises administering to the patient in need thereof about 20mg of compound 1 once per day.

Other embodiments of methods using the combinations provided herein are described below.

Brief Description of Drawings

FIG. 1 shows the percentage of median relative change (IQR) at week 12 for markers of fibrosis (ALT, AST, GGT, ALP, TIMP-1, PII-NP, and HA). For each marker, 3 columns are shown, with the left column corresponding to 20mg of compound 1, the middle column corresponding to 5mg of compound 1, and the right column corresponding to placebo.

Figure 2 shows the changes in MRI-PDFF and ALT during compound 1 treatment in subjects with compensated cirrhosis due to NASH. BL means baseline, W4 means week 4, and W12 means week 12.

Figure 3 shows the change in serum markers of liver biochemistry and fibrosis between baseline and week 12 from MRI-PDFF response as described in example 1. The data is the median value (IQR). For each marker, 2 columns are shown, with the left column corresponding to ≧ 30% reduction (n-33) and the right column corresponding to < 30% reduction (n-60).

Figure 4 shows the relative changes in plasma triglycerides in the animals studied. Values are expressed as the percentage of vehicle-treated animals collected at the same time of day after treatment with vehicle, compound 2 ("C2"), and compound 2 in combination with fenofibrate ("C2 + feno"). P.ltoreq.0.05, p.ltoreq.0.01, p.ltoreq.0.0001, n.ltoreq.27 to 38 per treatment group, and samples were taken from 8 to 13 animals. Data are presented as mean ± SEM.

Fig. 5A, 5B, and 5C show the levels of liver triglycerides, liver cholesterol, and plasma ketone bodies at2 hours or 24 hours post-administration in animals treated with vehicle ("Veh"), compound 2 ("C2"), and a combination of compound 2 and fenofibrate ("C2 + feno"), respectively. ns is not significant. P is 0.01 or less, p is 0.001 or less, p is 0.0001 or less, p # is 0.05 or less, p # is 0.001 or less, p # is 0.0001 or less, as compared to compound 2 treated mice, by unpaired student's t-test; each treatment group, n-7-20, was sampled from 7-10 animals. Data are presented as mean ± SEM.

fig. 6A and 6B show LXR α and SREBP1C targets, respectively, in animals treated with vehicle, compound 2 ("C2"), or a combination of compound 2 and fenofibrate ("C2 + feno").

Figure 7 shows the median relative change (%) of imaging, liver biochemistry, serum markers of fibrosis and triglyceride levels at week 12 for subjects administered 20mg of compound 1 and fibrate/fish oil (left column) compared to 20mg of compound 1 alone (right column), as described in example 4.

Fig. 8A shows triglycerides and ApoB48 from a patient administered 145mg fenofibrate after week 1 with high-grade hypertriglyceridemia.

Fig. 8B shows VLDL particle levels and ApoC3 for patients administered 145mg fenofibrate after week 1 with high grade 3 triglyceridemia.

Figure 9 shows the change in plasma triglycerides 2 hours post-dose in free-feeding Fast Food (FFD) mice treated with vehicle, single doses of fenofibrate ("Feno (25 mg/kg)" and "Feno (50 mg/kg)"), and compound 2 ("C2 (5 mg/kg)"), and a combination of compound 2 and fenofibrate (50mg/kg) "(" C2+ Feno (50mg/kg) "). P <0.05, p < 0.01, p <0.001, p < 0.0001, n-11-15 animals per treatment group. Data are presented as mean ± SD.

figures 10A and 10B show that hepatic mRNA expression for PPAR α and LXR α targets in animals treated with vehicle, single agents of fenofibrate ("Feno (25 mg/kg)" and "Feno (50 mg/kg)") and compound 2 ("C2 (5 mg/kg)"), and a combination of compound 2 and fenofibrate (50mg/kg) ("C2 + Feno (50 mg/kg)"), respectively,. p.ltoreq.0.05,. p.ltoreq.0.01,. p.ltoreq.0.001,. p.ltoreq.0.0001,. n.gtx.11-15 animals per treatment group.

Figures 11A and 11B show plasma ALT and AST levels in animals treated with vehicle, single doses of fenofibrate ("Feno (25 mg/kg)" and "Feno (50 mg/kg)") and compound 2 ("C2 (5 mg/kg)"), and a combination of compound 2 and fenofibrate (50mg/kg) ("C2 + Feno (50 mg/kg)"), respectively, for 15 days on a standard diet (food) or FFD. P <0.05, p < 0.01, p <0.001, p < 0.0001, n-10-15 animals per treatment group. Data are presented as mean ± SEM.

figures 12A and 12B show the levels of hepatic triglycerides and hepatic ketone bodies (β OHB) 2 hours post-administration, p ≦ 0.05, p ≦ 0.01, p ≦ 0.001, p ≦ 0.0001, ns ≦ insignificant, n ═ 11-15 animals per treatment group, data expressed as mean ± SD, in animals treated with vehicle, single doses of fenofibrate ("Feno (25 mg/kg)" and "Feno (50 mg/kg)") and compound 2 ("C2 (5 mg/kg)"), and a combination of compound 2 and fenofibrate (50mg/kg) ".

Figure 13 shows oxidative stress, quantified as the amount of malondialdehyde, in the liver of animals treated for 15 days with vehicle, single doses of fenofibrate ("Feno (25 mg/kg)" and "Feno (50 mg/kg)"), and compound 2 ("C2 (5 mg/kg)"), and a combination of compound 2 and fenofibrate (50mg/kg) "(" C2+ Feno (50mg/kg) "). P <0.05, p < 0.01, p <0.001, p < 0.0001, n-11-15 animals per treatment group. Data are presented as mean ± SD.

FIGS. 14A and 14B show mRNA expression of profibrotic genes col1a1 and timp1 in the livers of animals treated for 15 days with vehicle, single doses of fenofibrate ("Feno (25 mg/kg)" and "Feno (50 mg/kg)") and Compound 2 ("C2 (5 mg/kg)"), and a combination of Compound 2 and fenofibrate (50mg/kg) "(" C2+ Feno (50mg/kg) "), respectively. P <0.05, p < 0.01, p <0.001, p < 0.0001, n-11-15 animals per treatment group. Data are presented as mean ± SD.

Detailed Description

as described herein, in some embodiments, the present invention provides methods of treating, stabilizing or reducing the severity or progression of non-alcoholic fatty liver disease (NAFLD) comprising administering to a patient in need thereof a combination of an ACC inhibitor and a PPAR α agonist.

Definition of

The terms "comprise" and variations thereof, such as "comprises" and "comprising," are to be construed in an open, inclusive sense, i.e., "including, but not limited to. Also, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, reference to "an agent" includes a plurality of such agents.

As used herein, the term "about" in the context of quantitative measurements refers to ± 10%, or ± 5%, or ± 1% of the indicated quantity. For example, "about 30%" means 33% to 27%, or 31.5% to 28.5%, or 30.3% to 29.7%.

As used herein, generally, "ACC inhibitor" refers to any therapeutic agent that reduces the activity of acetyl CoA carboxylase enzyme.

As used herein, "non-alcoholic fatty liver disease" or "NAFLD" refers to any disease or other deleterious condition characterized and/or caused by excessive liver fat accumulation, including, but not limited to, steatosis, non-alcoholic steatohepatitis (NASH), NASH-induced liver fibrosis, NASH-induced cirrhosis, or NASH-induced hepatocellular carcinoma (HCC).

As used herein, "hypertriglyceridemia" refers to a condition in which blood triglyceride levels are elevated to abnormal levels.

The term "subject" or "patient," as used herein, refers to mammals, including humans and animal subjects, such as livestock (e.g., horses, dogs, cats, etc.).

As used herein, "therapeutically effective amount" refers to an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation), or a combination of two or more agents or compounds, or a sufficient amount of a single agent or compound in a combination of two or more agents or compounds, that will elicit the desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and/or delay the onset of NAFLD when administered as part of a dosing regimen to a subject suffering from or susceptible to NAFLD. As will be appreciated by one of ordinary skill in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance to be delivered, the target cell or tissue, and the like. For example, an effective amount of a compound in a formulation for treating NAFLD is an amount that reduces, ameliorates, alleviates, inhibits, prevents, delays the onset of, reduces the severity of, and/or reduces the incidence of one or more symptoms or features thereof. In some embodiments, a "therapeutically effective amount" is at least a minimum amount of a compound or composition containing the compound sufficient to treat one or more symptoms of NASH.

As used herein, the term "treating" refers to partially or completely alleviating, inhibiting, delaying onset, preventing, ameliorating and/or alleviating a disease or disorder or one or more symptoms of a disease or disorder. As used herein, the term "treating" refers to partial or complete alleviation, inhibition, delay of onset, prevention, amelioration and/or alleviation of one or more symptoms of NAFLD or NAFLD. In some embodiments, treatment may be administered after one or more symptoms have occurred. In some embodiments, the term "treating" includes preventing or arresting the progression of NAFLD. In other embodiments, treatment may be given without symptoms. For example, susceptible individuals may be treated prior to the onset of symptoms (e.g., based on history of symptoms and/or based on genetic or other susceptibility factors). Treatment may also be continued after remission, e.g., to prevent or delay recurrence thereof. Thus, in some embodiments, the term "treating" includes preventing recurrence or recurrence of NAFLD.

As used herein, the expression "unit dosage form" refers to physically discrete units of a therapeutic formulation suitable for the subject to be treated. It will be understood, however, that the total daily amount of the composition of the invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disease; the activity of the particular active agent used; the specific composition used; the age, weight, general health, sex, and diet of the subject; the time of administration and the rate of excretion of the particular active agent employed; the duration of treatment; drugs and/or other therapies used in combination or concomitantly with the specific compound employed and similar factors well known in the medical arts.

Method of treatment

in some embodiments, methods of treating, stabilizing or reducing the severity or progression of non-alcoholic fatty liver disease (NAFLD) are provided, wherein the methods comprise administering to a patient in need thereof a combination of an ACC inhibitor and a PPAR α agonistthe method comprises administering to a patient in need thereof a combination of an ACC inhibitor and a PPAR α agonist, wherein the PPAR α agonist is selected from the group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemofibrate, chlorofibrate, bisfibrate, an omega-3 fatty acid (e.g., ethyl eicosapentaenoate)

Or docosahexaenoic acid), piririnic acid, GW409544, AZ242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, and mogglicla.

In some aspects, methods of treating, stabilizing or reducing the severity or progression of non-alcoholic fatty liver disease (NAFLD) are provided, the methods comprising administering an ACC inhibitor and a fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b).

in some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NAFLD while reducing or eliminating the occurrence or reducing the severity of hypertriglyceridemia, wherein the methods comprise administering to a patient in need thereof a combination of an ACC inhibitor and a PPAR α agonist

docosahexaenoic acid, α -linolenic acid, hexadecatrienoic acid, stearidonic acid, and docosatetraenoic acidTridecenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, etc.), piritinic acid, GW409544, AZ242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, mogroside and saroglite.

In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NAFLD while reducing or eliminating the appearance of or reducing the severity of hypertriglyceridemia, wherein the methods comprise administering an ACC inhibitor with a fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b). In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NAFLD without substantially increasing plasma triglyceride levels in a patient, wherein the methods comprise administering an ACC inhibitor and a fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b).

in some embodiments, a method of treating, stabilizing or reducing the severity or progression of non-alcoholic fatty liver disease (NAFLD) is provided, the method comprising administering to a patient in need thereof a combination of compound 1 and a PPAR α agonist, wherein the method comprises administering to a patient in need thereof a combination of compound 1 and a PPAR α agonist, wherein the PPAR α agonist is selected from the group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemabelate, chloronicotinate, bisfibrate, omega-3 fatty acids (e.g., ethyl eicosapentaenoate)

Or docosahexaenoic acid), pimelic acid, GW409544, or mixtures thereof,AZ242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar and moggliclazide.

In some aspects, provided are methods of treating, stabilizing, or reducing the severity or progression of non-alcoholic fatty liver disease (NAFLD) comprising administering compound 1 in combination with fish oil to a patient in need thereof.

in some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NAFLD while reducing or eliminating the occurrence or severity of hypertriglyceridemia, wherein the methods comprise administering to a patient in need thereof a combination of compound 1 and a PPAR α agonist

Or docosahexaenoic acid), piririnic acid, GW409544, AZ242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, moggliclazide and saroglitazar.

In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NAFLD while reducing or eliminating the appearance of or reducing the severity of hypertriglyceridemia, wherein the method comprises administering compound 1 with fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b). In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NAFLD without substantially increasing plasma triglyceride levels in a patient, wherein the methods comprise administering to the patient a therapeutically effective amount of NAFLDAdministration of Compound 1 with fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b).

in some embodiments, a method of treating, stabilizing or reducing the severity or progression of non-alcoholic fatty liver disease (NAFLD) is provided, the method comprising administering to a patient in need thereof a combination of compound 2 and a PPAR α agonist, wherein the method comprises administering to a patient in need thereof a combination of compound 2 and a PPAR α agonist, wherein the PPAR α agonist is selected from the group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemabelate, chloronicotinate, bisfibrate, omega-3 fatty acids (e.g., ethyl eicosapentaenoate)

In some aspects, provided are methods of treating, stabilizing, or reducing the severity or progression of non-alcoholic fatty liver disease (NAFLD) comprising administering compound 2 in combination with fish oil to a patient in need thereof.

in some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NAFLD while reducing or eliminating the appearance or reducing the severity of hypertriglyceridemia, wherein the methods comprise administering to a patient in need thereof a combination of compound 2 and a PPAR α agonistCholine fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemofibrate, chlorofibrate, bisfibrate, omega-3 fatty acids (e.g., ethyl eicosapentaenoate)

In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NAFLD while reducing or eliminating the appearance of or reducing the severity of hypertriglyceridemia, wherein the method comprises administering compound 2 with fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b). In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NAFLD without substantially increasing plasma triglyceride levels in a patient, wherein the methods comprise administering compound 2 with fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b).

In some embodiments, the NAFLD is steatosis. In some embodiments, the NAFLD is nonalcoholic steatohepatitis (NASH). In some embodiments, the NAFLD is NASH-induced liver fibrosis. In some embodiments, the NAFLD is NASH-induced cirrhosis. In some embodiments, the NAFLD is NASH-induced hepatocellular carcinoma (HCC).

in some aspects, provided herein are methods of treating, stabilizing or reducing the severity or progression of NASH-induced liver fibrosis, wherein the method comprises administering to a patient in need thereof an ACC inhibitor in combination with a PPAR α agonistthe AR α agonist is selected from the group consisting of fish oil, aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemofibrate, chlorofibrate, bisfibrate, omega-3 fatty acids (e.g., ethyl eicosapentaenoate)

in some aspects, provided herein is a method of treating, stabilizing or reducing the severity or progression of nonalcoholic steatohepatitis (NASH), wherein the method comprises administering to a patient in need thereof a combination of an ACC inhibitor and a PPAR α agonist

In some aspects, provided herein are methods of treating, stabilizing or reducing the severity or progression of nonalcoholic steatohepatitis (NASH), wherein the methods comprise administering an ACC inhibitor and a fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b).

In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of nonalcoholic steatohepatitis (NASH)in some aspects, provided herein is a method of treating, stabilizing, or reducing the severity or progression of nonalcoholic steatohepatitis (NASH), wherein the method comprises administering to a patient in need thereof a combination of compound 1 and a PPAR α agonist, wherein the PPAR α agonist is selected from the group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemofibrate, chlorofibrate, bisfibrate, omega-3 fatty acids (e.g., ethyl eicosapentaenoate)

In some aspects, provided herein are methods of treating, stabilizing or reducing the severity or progression of nonalcoholic steatohepatitis (NASH), wherein the methods comprise administering compound 1 and a fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b).

in some aspects, provided herein is a method of treating, stabilizing or reducing the severity or progression of nonalcoholic steatohepatitis (NASH), wherein the method comprises administering to a patient in need thereof a combination of compound 2 and a PPAR α agonist, wherein the PPAR α agonist is selected from the group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemofibrate, chlorofibrate, bisfibrate, omega-3 fatty acids (e.g., ethyl eicosapentaenoate)

In some aspects, provided herein are methods of treating, stabilizing or reducing the severity or progression of nonalcoholic steatohepatitis (NASH), wherein the methods comprise administering compound 2 and a fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b).

In some embodiments, the patient is non-cirrhotic.

In some embodiments, the patient has grade 1-4 fibrosis by a historical liver biopsy.

● 1 level 1: enlarging the portal zone by fibrosis;

● 2 level 2: fibrosis extends from the portal areas with few bridges between the portal areas;

● 3 level 3: many fibrotic bridges connect the portal and central regions of the liver

● 4 level 4: definitive cirrhosis, biopsy fibrosis < 50%.

In some embodiments, the patient has a magnetic resonance imaging proton density fat fraction (MRI-PDFF) at baseline (prior to treatment with the ACC inhibitor of at least about 8%. In some embodiments, the patient has an MRI-PDFF at baseline of at least about 11%.

In some embodiments, the patient has a magnetic resonance imaging proton density fat fraction (MRI-PDFF) at baseline (prior to treatment with compound 1) of at least about 8%. In some embodiments, the patient has an MRI-PDFF at baseline of at least about 11%.

In some embodiments, the patient has a magnetic resonance imaging proton density fat fraction (MRI-PDFF) at baseline (prior to treatment with compound 2) of at least about 8%. In some embodiments, the patient has an MRI-PDFF at baseline of at least about 11%.

In some embodiments, the patient has a liver stiffness at baseline (prior to treatment with the ACC inhibitor) of at least about 2.5 kPa. In some embodiments, the patient has a liver stiffness at baseline of at least about 2.9 kPa.

In some embodiments, the patient has a liver stiffness at baseline (prior to treatment with compound 1) of at least about 2.5 kPa. In some embodiments, the patient has a liver stiffness at baseline of at least about 2.9 kPa.

In some embodiments, the patient has a liver stiffness at baseline (prior to treatment with compound 2) of at least about 2.5 kPa. In some embodiments, the patient has a liver stiffness at baseline of at least about 2.9 kPa.

In some embodiments, the patient has elevated serum levels of ALT, TIMP-1 and/or PIII-NP at baseline as compared to normal.

In some embodiments, the treatment reduces MRI-PDFF of the patient by at least about 20% compared to baseline. In some embodiments, the treatment reduces MRI-PDFF of the patient by at least about 25% compared to baseline. In some embodiments, the treatment reduces MRI-PDFF of the patient by at least about 30% compared to baseline.

In some embodiments, at least about one-third of the treated patients achieves a reduction in MRI-PDFF of about 30% compared to baseline. In some embodiments, about one-half of the treated patients achieved a reduction in MRI-PDFF of about 30% compared to baseline.

In some embodiments, the treatment reduces the serum level of a tissue inhibitor of metalloproteinase-1 (TIMP-1) in the patient by at least about 5% as compared to baseline (the serum level of TIMP-1 prior to treatment with the ACC inhibitor). In some embodiments, the treatment reduces the serum level of TIMP-1 in the patient by at least about 6% as compared to baseline. In some embodiments, the treatment reduces the serum level of TIMP-1 in the patient by at least about 7% as compared to baseline.

In some embodiments, the treatment reduces the serum level of a tissue inhibitor of metalloproteinase-1 (TIMP-1) in the patient by at least about 5% as compared to baseline (the serum level of TIMP-1 prior to treatment with compound 1). In some embodiments, the treatment reduces the serum level of TIMP-1 in the patient by at least about 6% as compared to baseline. In some embodiments, the treatment reduces the serum level of TIMP-1 in the patient by at least about 7% as compared to baseline.

In some embodiments, the treatment reduces the serum level of a tissue inhibitor of metalloproteinase-1 (TIMP-1) in the patient by at least about 5% as compared to baseline (the serum level of TIMP-1 prior to treatment with compound 2). In some embodiments, the treatment reduces the serum level of TIMP-1 in the patient by at least about 6% as compared to baseline. In some embodiments, the treatment reduces the serum level of TIMP-1 in the patient by at least about 7% as compared to baseline.

In some embodiments, the treatment reduces the serum level of N-terminal procollagen III-peptide (PIII-NP) in the patient by at least about 9% as compared to baseline (serum level of PIII-NP prior to treatment with the ACC inhibitor). In some embodiments, the treatment reduces serum levels of PIII-NP in the patient by at least about 10% as compared to baseline. In some embodiments, the treatment reduces serum levels of PIII-NP in the patient by at least about 13% as compared to baseline.

In some embodiments, the treatment reduces the serum level of N-terminal procollagen III-peptide (PIII-NP) in the patient by at least about 9% as compared to baseline (serum level of PIII-NP prior to treatment with compound 1). In some embodiments, the treatment reduces serum levels of PIII-NP in the patient by at least about 10% as compared to baseline. In some embodiments, the treatment reduces serum levels of PIII-NP in the patient by at least about 13% as compared to baseline.

In some embodiments, the treatment reduces the serum level of N-terminal procollagen III-peptide (PIII-NP) in the patient by at least about 9% as compared to baseline (serum level of PIII-NP prior to treatment with compound 2). In some embodiments, the treatment reduces serum levels of PIII-NP in the patient by at least about 10% as compared to baseline. In some embodiments, the treatment reduces serum levels of PIII-NP in the patient by at least about 13% as compared to baseline.

in some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NASH while reducing or eliminating the occurrence or severity of hypertriglyceridemia, wherein the methods comprise administering to a patient in need thereof a combination of an ACC inhibitor and a PPAR α agonist

Or docosahexaenoic acid), GW409544, AZ242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, moggliclazide and saloglutazide.

In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NASH while reducing or eliminating the appearance of or reducing the severity of hypertriglyceridemia, wherein the methods comprise administering an ACC inhibitor and a fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b). In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NASH without substantially increasing plasma triglyceride levels in a patient, wherein the methods comprise administering an ACC inhibitor and a fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b).

in some aspects, provided herein is a method of treating, stabilizing, or reducing the severity or progression of NASH while reducing or eliminating the occurrence or severity of hypertriglyceridemia, wherein the method comprises administering to a patient in need thereof a combination of compound 1 and a PPAR α agonist

In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NASH while reducing or eliminating the appearance of, or reducing the severity of, hypertriglyceridemia, wherein the methods comprise administering compound 1 and fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b). In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NASH without substantially increasing plasma triglyceride levels in a patient, wherein the methods comprise administering compound 1 and fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b).

In some aspects, provided herein is a method of treating, stabilizing, or reducing the severity or progression of NASHin some embodiments, the PPAR α agonist is selected from the group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemofibrate, chloronicotinate, bisfibrate, omega-3 fatty acids (e.g., ethyl eicosapentaenoate), and the like

In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NASH while reducing or eliminating the appearance of or reducing the severity of hypertriglyceridemia, wherein the methods comprise administering compound 2 with fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b). In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NASH without substantially increasing plasma triglyceride levels in a patient, wherein the methods comprise administering compound 2 and a fish oil, e.g., ethyl eicosapentaenoate, to a patient in need thereof

Combinations of (a) and (b).

In some embodiments, the patient is non-cirrhotic. In some embodiments, the patient has a magnetic resonance imaging proton density fat fraction (MRI-PDFF) at baseline (prior to treatment with the ACC inhibitor of at least about 8%. In some embodiments, the patient has an MRI-PDFF at baseline of at least about 11%.

In some embodiments, the patient is non-cirrhotic. In some embodiments, the patient has a magnetic resonance imaging proton density fat fraction (MRI-PDFF) at baseline (prior to treatment with compound 1) of at least about 8%. In some embodiments, the patient has an MRI-PDFF at baseline of at least about 11%.

In some embodiments, the patient is non-cirrhotic. In some embodiments, the patient has a magnetic resonance imaging proton density fat fraction (MRI-PDFF) at baseline (prior to treatment with compound 2) of at least about 8%. In some embodiments, the patient has an MRI-PDFF at baseline of at least about 11%.

In some embodiments, the patient has a normal plasma triglyceride level of less than about 150 milligrams per deciliter (mg/dL) at baseline (prior to treatment with the ACC inhibitor). In some embodiments, the patient has at least a critical high point plasma triglyceride level (about 150mg/dL or greater) at baseline. In some embodiments, the patient has at least about 500mg/dL or greater high plasma triglyceride levels at baseline. In some embodiments, the patient has a critical high point plasma triglyceride level of 150mg/dL to 199 mg/dL. In some embodiments, the patient has high plasma triglyceride levels of 200mg/dL to 499 mg/dL. In some embodiments, the patient has very high plasma triglyceride levels above 500 mg/dL. In some embodiments, the patient has plasma triglyceride levels at baseline of about 250 mg/dL.

In some embodiments, the patient has plasma triglyceride levels at baseline (prior to treatment with compound 1) of less than about 150 mg/dL. In some embodiments, the patient has plasma triglyceride levels at baseline of at least about 150 mg/dL. In some embodiments, the patient has plasma triglyceride levels at baseline of at least about 200 mg/dL. In some embodiments, the patient has plasma triglyceride levels at baseline of at least about 250 mg/dL.

In some embodiments, the patient has plasma triglyceride levels at baseline (prior to treatment with compound 2) of less than about 100 mg/dL. In some embodiments, the patient has plasma triglyceride levels at baseline of at least about 150 mg/dL. In some embodiments, the patient has plasma triglyceride levels at baseline of at least about 200 mg/dL. In some embodiments, the patient has plasma triglyceride levels at baseline of at least about 250 mg/dL.

in some embodiments, provided herein are methods of treating, stabilizing or reducing the severity or progression of NASH in a patient having NASH and plasma triglyceride levels below about 150mg/dL without substantially increasing the triglyceride levels in the patient, wherein the method comprises administering to the patient in need thereof a combination of an ACC inhibitor and a PPAR α agonist

Combinations of (a) and (b). In some embodiments, the patient has plasma triglyceride levels at baseline of at least about 150 mg/dL. In some embodiments, the patient has plasma triglyceride levels at baseline of at least about 200 mg/dL. In some embodiments, the patient has plasma triglyceride levels at baseline of at least about 250 mg/dL.

in some embodiments, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NASH in a patient having NASH and plasma triglyceride levels of at least about 150mg/dL without substantially increasing the triglyceride levels in the patient, wherein the method comprises administering compound 1 in combination with a PPAR α agonist to a patient in need thereof

Combinations of (a) and (b). In some embodiments, the patient has plasma triglyceride levels at baseline of at least about 200 mg/dL. In some embodiments, the patient has plasma triglyceride levels at baseline of at least about 250 mg/dL.

in some embodiments, provided herein are methods of treating, stabilizing, or reducing the severity or progression of NASH in a patient having NASH and plasma triglyceride levels of at least about 150mg/dL without substantially increasing the triglyceride levels in the patient, wherein the method comprises administering to a patient in need thereof a combination of compound 2 and a PPAR α agonist

In some embodiments, the triglyceride level of the treated patient is not significantly increased in the treatment. In some embodiments, the triglyceride level of the treated patient does not increase more than about 10% from baseline over the course of treatment. In some embodiments, the triglyceride level of the treated patient does not increase more than about 5% from baseline over the course of treatment. In some embodiments, the triglyceride level of the treated patient does not increase more than about 1% from baseline over the course of treatment. In some embodiments, the triglyceride level of the treated patient remains substantially the same after treatment, e.g., remains at about ± 10% of baseline or about ± 5% of baseline.

In some embodiments, the treated patient does not experience a grade 3 or 4 triglyceride rise.

in some embodiments, the PPAR α agonist is selected from the group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemofibrate, chlorofibrate, bisfibrate, omega-3 fatty acids (e.g., ethyl eicosapentaenoate)

or docosahexaenoic acid), pirfenic acid, GW409544, AZ242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, moglitazar, and saroglitazar.

in some embodiments, the ACC inhibitor (e.g., compound 1 or compound 2) is administered in a therapeutically effective amount.

it is expected that ACC inhibitors such as compound 1 or compound 2 in combination with PPAR α agonists (e.g., fish oil) improve markers of NASH including, but not limited to (e.g., ALT, AST, GGT, ELF, hyaluronic acid, TIMP1, PIIINP, TG, MRI-PDFF, MRE, and fibriscan.) it is also expected that patients receiving PPAR α agonists (e.g., fish oil) show an improvement in metabolic parameters (e.g., reduced triglycerides) at baseline when ACC inhibitors are administered.

In some aspects, provided herein are methods of treating non-alcoholic steatohepatitis in a non-cirrhosis patient having non-alcoholic steatohepatitis, wherein the method comprises administering to a patient in need thereof about 20mg per day of an ACC inhibitor.

In some aspects, provided herein is a method of treating non-alcoholic steatohepatitis in a non-cirrhosis patient having non-alcoholic steatohepatitis, wherein the method comprises administering to a patient in need thereof once daily about 20mg of compound 2.

In some aspects, provided herein are methods of treating nonalcoholic steatohepatitis (NASH) in a patient having compensated cirrhosis due to NASH. In some aspects, the method comprises administering an ACC inhibitor, including, but not limited to, compound 1 and compound 2. The method includes administration may be once daily and the daily dose may be, but is not limited to, 20 mg.

In some aspects, provided herein are methods of treating nonalcoholic steatohepatitis (NASH) in a patient having compensated cirrhosis due to NASH, wherein the method comprises administering to the patient in need thereof about 20mg of an ACC inhibitor once per day.

In some aspects, provided herein are methods of treating nonalcoholic steatohepatitis (NASH) in a patient having compensated cirrhosis due to NASH, wherein the method comprises administering to the patient in need thereof about 20mg of compound 2 once per day.

In some aspects, provided herein are methods of ameliorating hepatic steatosis in a patient having compensated cirrhosis due to NASH. In some aspects, provided herein are methods of ameliorating hepatic steatosis in a non-cirrhosis patient with NASH.

In some embodiments, the patient has a magnetic resonance imaging proton density fat fraction (MRI-PDFF) at baseline (prior to treatment with the compound ACC inhibitor) of at least about 8%. In some embodiments, the patient has an MRI-PDFF at baseline of at least about 11%.

In some embodiments, the patient has a baseline plasma triglyceride level of less than about 250 mg/dL. In some embodiments, the patient has a baseline plasma triglyceride level of less than about 200 mg/dL. In some embodiments, the patient has a baseline plasma triglyceride level of less than about 150 mg/dL.

In some embodiments, the treatment reduces the magnetic resonance imaging proton density fat fraction (MRI-PDFF) of the patient by at least about 20% compared to baseline. In some embodiments, the treatment reduces MRI-PDFF of the patient by at least about 25% compared to baseline. In some embodiments, the treatment reduces MRI-PDFF of the patient by at least about 30% compared to baseline.

In some embodiments, a reduction in MRI-PDFF of about 30% is achieved in at least about one-third of patients treated with ACC inhibitors compared to baseline. In some embodiments, a reduction in MRI-PDFF of about 30% is achieved in about one-half of patients treated with ACC inhibitors compared to baseline.

In some embodiments, a reduction in MRI-PDFF of about 30% is achieved in at least about one-third of patients treated with compound 1 compared to baseline. In some embodiments, a reduction in MRI-PDFF of about 30% is achieved in about one-half of patients treated with compound 1 compared to baseline.

In some embodiments, a reduction in MRI-PDFF of about 30% is achieved in at least about one third of patients treated with compound 2 compared to baseline. In some embodiments, a reduction in MRI-PDFF of about 30% is achieved in about one-half of patients treated with compound 2 compared to baseline.

In some embodiments, the treatment reduces the serum level of a tissue inhibitor of metalloproteinase-1 (TIMP-1) in the patient by at least about 5% (the serum level of TIMP-1 prior to treatment) as compared to baseline. In some embodiments, the treatment reduces the serum level of TIMP-1 in the patient by at least about 6% as compared to baseline. In some embodiments, the treatment reduces the serum level of TIMP-1 in the patient by at least about 7% as compared to baseline.

In some embodiments, the treatment reduces serum levels of N-terminal procollagen III-peptide (PIII-NP) in the patient by at least about 9% (serum levels of PIII-NP prior to treatment) as compared to baseline. In some embodiments, the treatment reduces serum levels of PIII-NP in the patient by at least about 10% as compared to baseline. In some embodiments, the treatment reduces serum levels of PIII-NP in the patient by at least about 13% as compared to baseline.

in some embodiments, the method further comprises administering to the patient a PPAR α agonist or fish oil.

In some embodiments, there is provided a method of reducing hepatic diacylglycerol levels in a patient in need thereof having elevated hepatic diacylglycerol levels, wherein the method comprises administering to the patient a therapeutically effective amount of an ACC inhibitor.

In some embodiments, there is provided a method of restoring liver membrane lipids in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of an ACC inhibitor.

In some embodiments, there is provided a method of increasing liver phosphatidylethanolamine in a patient in need thereof with decreased liver phosphatidylethanolamine levels, wherein the method comprises administering to the patient a therapeutically effective amount of an ACC inhibitor.

In some embodiments, there is provided a method of increasing hepatic phosphatidylcholine in a patient in need thereof having decreased hepatic phosphatidylcholine levels, wherein the method comprises administering to the patient a therapeutically effective amount of an ACC inhibitor.

In some embodiments, there is provided a method of reducing a bile acid synthesis substrate in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of an ACC inhibitor.

In some embodiments, a method of treating NASH in a patient having an elevated level of one or more of Col1a1, palmitoleate, isobutyryl carnitine, 3-hydroxybutyrate, or 3-hydroxybutyryl carnitine is provided, wherein the method comprises administering to the patient a therapeutically effective amount of an ACC inhibitor.

In some embodiments, the ACC inhibitor is administered in an amount of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, or about 35mg per day. In some embodiments, the ACC inhibitor is administered once, twice or three times daily. In some embodiments, the ACC inhibitor is administered in an amount of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, or about 35mg once per day.

In some embodiments, compound 1 is administered in an amount of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, or about 35mg per day. In some embodiments, compound 1 is administered once, twice or three times daily. In some embodiments, compound 1 is administered in an amount of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, or about 35mg once daily. In some embodiments, compound 1 is administered in an amount of about 20mg once daily. In some embodiments, compound 1 is (R) -2- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidine-3 (4H) -one-carboxylic acid as the free acid

Yl) -2-methylpropionic acid in an amount of about 20mg once a day. In some embodiments, Compound 1 is administered as a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal of (R) -2- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) -2-methylpropionic acid once per day in an amount equal to about 20mg of (R) -2- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) -2-methylpropionic acid free acid.

In some embodiments, compound 2 is administered in an amount of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, or about 35mg per day. In some embodiments, compound 2 is administered once, twice or three times daily. In some embodiments, compound 2 is administered in an amount of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, or about 35mg once daily. In some embodiments, compound 2 is administered in an amount of about 20mg once daily. In some embodiments, compound 2 is administered as the free acid 2- [1- [ (2R) -2- [ (4-hydroxycyclohexyl) oxy ] -2- (2-methoxyphenyl) ethyl ] -5-methyl-6- (1, 3-oxazol-2-yl) -2, 4-dioxo-1H, 2H,3H, 4H-thieno [2,3-d ] pyrimidin-3-yl ] -2-methylpropionic acid in an amount of about 20mg once per day. In some embodiments, compound 2 is administered as a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal of 2- [1- [ (2R) -2- [ (4-hydroxycyclohexyl) oxy ] -2- (2-methoxyphenyl) ethyl ] -5-methyl-6- (1, 3-oxazol-2-yl) -2, 4-dioxo-1H, 2H,3H, 4H-thieno [2,3-d ] pyrimidin-3-yl ] -2-methylpropionic acid, once per day in an amount equal to about 20mg of 2- [1- [ (2R) -2- [ (4-hydroxycyclohexyl) oxy ] -2- (2-methoxyphenyl) ethyl ] -5-methyl-6- (1, 3-oxazol-2-yl) -2, 4-dioxo-1H, 2H,3H, 4H-thieno [2,3-d ] pyrimidin-3-yl ] -2-methylpropionic acid free acid.

In some embodiments, the ACC inhibitor is administered in a unit dosage formulation comprising an ACC inhibitor in an amount equal to about 10mg, 20mg, or 30mg of the free acid of the ACC inhibitor. In certain embodiments, the capsule formulation provides an amount of ACC inhibitor equal to about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, or about 35mg of the free acid of ACC inhibitor.

In some embodiments, compound 1 is administered as a unit dose formulation comprising an amount of compound 1 equal to about 10mg, 20mg, or 30mg of compound 1 free acid. In certain embodiments, the capsule formulation provides an amount of compound 1 equal to about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, or about 35mg of compound 1 free acid.

In some embodiments, compound 2 is administered in a unit dose formulation comprising an amount of compound 2 equal to about 10mg, 20mg, or 30mg of compound 2 free acid. In certain embodiments, the capsule formulation provides an amount of compound 2 equal to about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, or about 35mg of compound 2 free acid.

In some embodiments, the once-daily ACC inhibitor is administered in the evening, such as at a local time of about 6p.m., about 7p.m., about 8p.m., or about 9p.m., or thereafter.

In some embodiments, the once daily administration of compound 1 is in the evening, such as about 6p.m., about 7p.m., about 8p.m., or about 9p.m., or later at a local time.

In some embodiments, the once daily administration of compound 2 is in the evening, such as about 6p.m., about 7p.m., about 8p.m., or about 9p.m., or later at a local time.

In some embodiments, the treatment is administered after the onset of one or more symptoms. In other embodiments, the treatment is administered without a symptom. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (e.g., based on history of symptoms and/or based on genetic or other susceptibility factors). Treatment may also be continued after remission, e.g., to prevent, delay or lessen the severity of its recurrence.

Compound 1

Compound 1 is an ACC inhibitor having the chemical name (R) -2- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) -2-methylpropionic acid and the following structure:

or a pharmaceutically acceptable salt, co-crystal, solvate or hydrate thereof. In some embodiments, compound 1 is (R) -2- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) -2-methylpropionic acid, which is also referred to as compound 1 free acid. In some embodiments, compound 1 is a pharmaceutically acceptable salt of (R) -2- (1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 2-dihydrothieno [2,3-d ] pyrimidin-3 (4H) -yl) -2-methylpropionic acid. In some embodiments, deuterated analogs of compound 1 can be used in the methods described herein.

Examples of pharmaceutically acceptable salts include salts derived from suitable bases, including metal ions (e.g., aluminum, zinc, alkali metals, alkaline earth metals), ammonium, and N⁺(C_1–4Alkyl radical)₄A salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, if appropriate, salts derived from nontoxic ammonium, quaternary ammonium, and primary, secondary or tertiary amine cations, including, but not limited to, salts derived from naturally or non-naturally occurring amino acids. Representative amine or ammonium based salts include, but are not limited to, those derived from arginine, betaine, hydrabamine, choline, diethylamine, lysine, benzathine, 2- (diethylamino) -ethanol, arginine, glycine, alanine, glycine, lysine, arginine, glycine, lysine,salts of ethanolamine, 1- (2-hydroxyethyl) -pyrrolidine, diethanolamine, ammonia, dimethylaminoethanol (deanol), N-methyl-glucamine, tromethamine, triethanolamine, 4- (2-hydroxyethyl) -morpholine, 1H-imidazole, ethylenediamine, piperazine, procaine and benzphetamine.

In some embodiments, compound 1 is in a crystalline form. Certain crystalline forms of compound 1 are described in U.S. patent application publication US2017/0267690a1, which is incorporated herein by reference in its entirety. In some embodiments, the crystalline form of compound 1 is "compound 1 form I", "compound 1 form II", "compound 1 form III", "compound 1 form IV", "compound 1 form V", "compound 1 form VI", "compound 1 form VII", "compound 1 form VIII" as described in US2017/0267690a 1.

In some embodiments, compound 1 is "compound 1 sodium form I", "compound 1 sodium form II", "compound 1 calcium form I", "compound 1 magnesium form I", "compound 1 diethanolamine form I", or "compound 1 piperazine form I", as described in US2017/0267690a 1.

in some embodiments, the crystalline form of compound 1 is compound 1 form I, characterized by an X-ray powder diffraction pattern comprising peaks at 9.3, 15.0, and 19.8 ° 2 θ ± 0.2 ° 2 θ, as measured by diffractometry using Cu-K α radiation at a wavelength of

And (4) measuring.

In some embodiments, compound 1 form I is characterized by a diffractogram comprising one or more additional peaks at 16.0, 24.0, 25.8, and 27.3 ° 2 Θ ± 0.2 ° 2 Θ.

In some embodiments, the crystalline form of compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from: about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2 θ.

In some embodiments, compound 1 form 1 is characterized by a Differential Scanning Calorimetry (DSC) curve that comprises an endotherm at about 189 ℃ to about 193 ℃.

In some embodiments, the crystalline form of compound 1 is at least about 85% form I.

In some embodiments, the crystalline form of compound 1, or a pharmaceutically acceptable salt or co-crystal thereof, is selected from compound 1 form II, compound 1 form III, compound 1 form IV, compound 1 form V, compound 1 form VI, compound 1 form VII, compound 1 form VIII, compound 1 sodium form I, compound 1 sodium form II, compound 1 calcium form I, compound 1 magnesium form I, compound 1 diethanolamine form I, and compound 1 piperazine form I.

In some embodiments, compound 1 is in amorphous form. In some embodiments, compound 1 is substantially free of crystalline compound 1.

Compound 2

Compound 2 is an ACC inhibitor having the chemical name 2- [1- [ (2R) -2- [ (4-hydroxycyclohexyl) oxy ] -2- (2-methoxyphenyl) ethyl ] -5-methyl-6- (1, 3-oxazol-2-yl) -2, 4-dioxo-1H, 2H,3H, 4H-thieno [2,3-d ] pyrimidin-3-yl ] -2-methylpropionic acid and the following structure:

or a pharmaceutically acceptable salt, co-crystal, solvate or hydrate thereof. In some embodiments, compound 2 is 2- [1- [ (2R) -2- [ (4-hydroxycyclohexyl) oxy ] -2- (2-methoxyphenyl) ethyl ] -5-methyl-6- (1, 3-oxazol-2-yl) -2, 4-dioxo-1H, 2H,3H, 4H-thieno [2,3-d ] pyrimidin-3-yl ] -2-methylpropionic acid, which is also referred to as compound 2 free acid. In some embodiments, compound 2 is a pharmaceutically acceptable salt of 2- [1- [ (2R) -2- [ (4-hydroxycyclohexyl) oxy ] -2- (2-methoxyphenyl) ethyl ] -5-methyl-6- (1, 3-oxazol-2-yl) -2, 4-dioxo-1H, 2H,3H, 4H-thieno [2,3-d ] pyrimidin-3-yl ] -2-methylpropionic acid. In some embodiments, deuterated analogs of compound 2 can be used in the methods described herein.

PPAR α agonists

as described above, the provided methods include combinations comprising an ACC inhibitor, e.g., compound 1 or compound 2, and a peroxisome proliferator-activated receptor alpha (PPAR α) agonist.

peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors, including three subtypes, PPARalpha, PPARgamma and PPARdelta, cloned from mice and humans

PPAR α is also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1).

in some embodiments, the PPAR α agonist is not a mixed PPAR α/δ agonist, such as gft 505. in some embodiments, the PPAR α 0 agonist is not a PPAR α/γ dual agonist, such as saroglitaza. in some embodiments, the PPAR α agonist is a selective PPAR α agonist, such as a PPAR α agonist that is at least about 10-fold, about 20-fold, about 50-fold, or about 100-fold selective for PPAR α over PPAR γ and PPAR δ.

in some embodiments, the PPAR α agonist is selected from:

in some embodiments, the PPAR α agonist is a fibrate, a carbazole-based compound, or a piperidine-based compound.

fibrates are a class of amphiphilic carboxylic compounds including, for example, aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemofibrate, chloronicotinate, and bisfibrate carbazole-based PPAR α agonists include, for example, the compounds described in U.S. patent application publication No. 2010/0286210, for example:

U.S. patent application publication No. 2010/0286210 is incorporated herein by reference in its entirety.

Piperidine-based compounds include those described in Christopher D.Kane et al, Molecular Pharmacology, 2009, 75(2):296-306 (incorporated herein by reference in their entirety), e.g., as described in

in some embodiments, the PPAR α agonist is a compound described in international patent application WO2017044551 (which is incorporated herein by reference in its entirety), e.g.

in some embodiments, the PPAR α agonist is an omega-3 fatty acid (e.g., ethyl eicosapentaenoate)

docosahexaenoic acid) in some embodiments, the PPAR α agonist is docosahexaenoic acid (DHA) in some embodiments, the PPAR α agonist is ethyl eicosapentaenoate in some embodiments, the omega-3 fatty acids are administered in a composition comprising omega-3 fatty acids such as fish oilIn another aspect, the methods described herein comprise administering to a patient in need thereof an ACC inhibitor, e.g., compound 1 or compound 2, in combination with fish oil.

in some embodiments, the PPAR α agonists are compounds described in U.S. patent application publication US20070197615 (which is incorporated herein by reference in its entirety), such as NS-220.

in some embodiments, the PPAR α agonist is fenofibrate, in some embodiments, the fenofibrate is administered in a dose of about 30mg to about 200mg per day, in some embodiments, the fenofibrate is administered in a dose of about 30mg to about 200mg once per day, in some embodiments, the fenofibrate is administered in a dose of about 30 to about 67mg, about 40 to about 54mg, about 40mg to about 200mg, about 50 to about 150mg, about 90 to about 200mg, about 120 to about 160mg, about 50mg, or about 150mg once per day, in some embodiments, the fenofibrate is administered orally.

in some embodiments, the dose of bezafibrate administered is about 600mg per day.

in some embodiments, the PPAR α agonist is ciprofibrate in a dose of about 100mg per day.

in some embodiments, clofibrate is administered in a dose of about 500mg orally 4 times daily.

in some embodiments, the PPAR α agonist is gemfibrozil, in some embodiments, gemfibrozil is administered in a dose of about 600mg orally 2 times per day, in some embodiments, gemfibrozil is administered 30 minutes prior to breakfast and dinner.

in some embodiments, the PPAR α agonist is pemfibrate, and in some embodiments, pemfibrate is administered in a dose of about 0.1mg to about 0.2mg 2 times daily.

in some embodiments, the PPAR α agonist is a PPAR α/γ dual agonist, including GW409544, AZ242, LY518674, and glitazar, such as aleglitazar, moglitazar (muraglitazar), and saroglitazar.

Other therapeutic agents

in certain embodiments, the one or more additional therapeutic agents are independently selected from the group consisting of angiotensin II receptor antagonists, Angiotensin Converting Enzyme (ACE) inhibitors, autotaxin inhibitors, caspase inhibitors, cathepsin B inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulators, cholesterol solubilizing agents, diacylglycerol O-acyltransferase 1(DGAT1) inhibitors, diacylglycerol O-acyltransferase 2(DGAT2) inhibitors, dipeptidyl peptidase IV (DPPIV) inhibitors, Farnesoid X Receptor (FXR) agonists, FXR/TGR5 dual agonists, galectin-3 inhibitors, glucagon-like peptide 1(GLP1) agonists, 36precursors, propion NS virus NS 24 protease inhibitors, HMG CoA reductase inhibitors, 11 β -hydroxysteroid dehydrogenase (11 β -hydroxysteroid dehydrogenase) inhibitors, inhibitors of glucagon-like peptide 1(GLP1) agonists, inhibitors of the enzyme kinase receptor kinase, inhibitors of ghrelin 2, inhibitors of the enzyme receptor kinase receptor, inhibitors of the enzyme receptor for the growth factor alfa 2, inhibitors of hepcidin receptor kinase, inhibitors of the enzyme receptor for the growth factor alfa receptor, inhibitors of the enzyme receptor for the proliferation of the thyroid receptor, ghrelin receptor, inhibitors of the enzyme receptor kinase receptor, ghrelin 2, inhibitors of the hormone receptor genes, ghrelin 465, inhibitors of the genes of ghrelin receptor, ghrelin 2, inhibitors of the genes, ghrelin receptor genes of the genes, ghrelin receptor genes, ghrelin 465, inhibitors of ghrelin receptor genes, ghrelin receptor genes of the genes.

In some embodiments, the additional therapeutic agent is an angiotensin II receptor antagonist.

In some embodiments, the additional therapeutic agent is an Angiotensin Converting Enzyme (ACE) inhibitor. In some embodiments, the ACE inhibitor is enalapril.

In some embodiments, the additional therapeutic agent is a caspase inhibitor. In some embodiments the caspase inhibitor is enrichloron.

In some embodiments, the additional therapeutic agent is a cathepsin B inhibitor. In some embodiments the cathepsin B inhibitor is a mixed cathepsin B/hepatitis c virus NS3 protease inhibitor. In some embodiments, the mixed cathepsin B/hepatitis c virus NS3 protease inhibitor is VBY-376.

In some embodiments, the additional therapeutic agent is a CCR2 chemokine antagonist. In some embodiments, the additional therapeutic agent is a mixed CCR2/CCR5 chemokine antagonist. In some embodiments, the mixed CCR2/CCR5 chemokine antagonist is a cericiviroc.

In some embodiments, the additional therapeutic agent is a CCR5 chemokine antagonist.

In some embodiments, the additional therapeutic agent is a chloride channel stimulator. In some embodiments, the chloride channel stimulant is cobiprostone (cobiprostone).

In some embodiments, the additional therapeutic agent is a cholesterol solubilizing agent.

In some embodiments, the additional therapeutic agent is a diacylglycerol O-acyltransferase 1(DGAT1) inhibitor. In some embodiments, the DGAT1 inhibitor is LCQ 908.

In some embodiments, the additional therapeutic agent is a dipeptidyl peptidase IV (DPPIV) inhibitor. In some embodiments, the DPPIV inhibitor is linagliptin.

In some embodiments, the additional therapeutic agent is a Farnesoid X Receptor (FXR) agonist. In some embodiments, the FXR agonist is INT-747 (obeticholic acid). In some embodiments, the FXR agonist is PX-102.

In some embodiments, the additional therapeutic agent is a FXR/TGR5 dual agonist. In some embodiments, the FXR/TGR5 dual agonist is INT-767.

In some embodiments, the additional therapeutic agent is a galectin-3 inhibitor. In some embodiments, the galectin-3 inhibitor is GR-MD-02.

In some embodiments, the additional therapeutic agent is a glucagon-like peptide 1(GLP1) agonist. In some embodiments, the GLP1 agonist is liraglutide. In some embodiments, the GLP1 agonist is exenatide.

In some embodiments, the additional therapeutic agent is a glutathione precursor.

In some embodiments, the additional therapeutic agent is a hepatitis c virus NS3 protease inhibitor. In some embodiments the hepatitis c virus NS3 protease inhibitor is a mixed cathepsin B/hepatitis c virus NS3 protease inhibitor. In some embodiments, the mixed cathepsin B/hepatitis c virus NS3 protease inhibitor is VBY-376.

In some embodiments, the additional therapeutic agent is an HMG CoA reductase inhibitor. In some embodiments, the HMG-CoA reductase inhibitor is a statin. In some embodiments, the HMG-CoA reductase inhibitor is atorvastatin.

in some embodiments, the additional therapeutic agent is an inhibitor of 11 β -hydroxysteroid dehydrogenase (11 β -HSD1) in some embodiments, the inhibitor of 11 β -HSD1 is RO 5093151.

in some embodiments, the additional therapeutic agent is an IL-1 β antagonist.

in some embodiments, the IL-6 antagonist is a mixed IL-6/IL-1 β/TNF α ligand inhibitor, in some embodiments, the mixed IL-6/IL-1 β/TNF α ligand inhibitor is BLX-1002.

In some embodiments, the additional therapeutic agent is an IL-10 agonist. In some embodiments, the IL-10 agonist is a peg-ilointerleukin.

In some embodiments, the additional therapeutic agent is an IL-17 antagonist. In some embodiments, the IL-17 antagonist is KD-025.

In some embodiments, the additional therapeutic agent is an ileal sodium bile acid cotransporter inhibitor. In some embodiments, the ileal sodium bile cotransporter inhibitor is SHP-626.

In some embodiments, the additional therapeutic agent is a leptin analog. In some embodiments the leptin analog is metreleptin.

In some embodiments, the additional therapeutic agent is a 5-lipoxygenase inhibitor. In some embodiments, the 5-lipoxygenase inhibitor is a mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitor. In some embodiments, the mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitor is tylolast.

In some embodiments, the additional therapeutic agent is an LPL gene stimulator. In some embodiments the LPL gene stimulator is tipader-glauca.

In some embodiments, the additional therapeutic agent is a lysyl oxidase homolog 2(LOXL2) inhibitor. In some embodiments, the LOXL2 inhibitor is an anti-LOXL 2 antibody. In some embodiments, the anti-LOXL 2 antibody is GS-6624 (simtuzumab).

In some embodiments, the additional therapeutic agent is a PDE3 inhibitor. In some embodiments, the PDE3 inhibitor is a mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitor. In some embodiments, the mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitor is tylolast.

In some embodiments, the additional therapeutic agent is a PDE4 inhibitor. In some embodiments, the PDE4 inhibitor is ASP-9831. In some embodiments, the PDE4 inhibitor is a mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitor. In some embodiments, the mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitor is tylolast.

In some embodiments, the additional therapeutic agent is a phospholipase C (PLC) inhibitor. In some embodiments, the PLC inhibitor is a mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitor. In some embodiments, the mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitor is tylolast.

In some embodiments, the additional therapeutic agent is a Rho-associated protein kinase 2(ROCK2) inhibitor. In some embodiments the ROCK2 inhibitor is KD-025.

In some embodiments, the additional therapeutic agent is a sodium glucose transporter-2 (SGLT2) inhibitor. In some embodiments, the SGLT2 inhibitor is remogliflozin etabonate.

In some embodiments, the additional therapeutic agent is a stearoyl-CoA desaturase-1 inhibitor. In some embodiments, the stearoyl-CoA desaturase-1 inhibitor is aramchol. In some embodiments, the stearoyl-CoA desaturase-1 inhibitor is CVT-12805.

in some embodiments the thyroid hormone receptor β agonist is MGL-3196.

in some embodiments, the additional therapeutic agent is a tumor necrosis factor alpha (TNF α) ligand inhibitor.

In some embodiments, the additional therapeutic agent is a transglutaminase inhibitor. In some embodiments, the transglutaminase inhibitor precursor is cysteamine.

In some embodiments, the additional therapeutic agent is a transglutaminase inhibitor precursor.

In some embodiments, the additional therapeutic agent is a PTP1b inhibitor. In some embodiments, the PTP1b inhibitor is A119505, A220435, A321842, CPT633, ISIS-404173, JTT-551, MX-7014, MX-7091, MX-7102, NNC-521246, OTX-001, OTX-002, or TTP 814.

In some embodiments, the additional therapeutic agent is an ASK1 inhibitor. In some embodiments, the ASK1 inhibitor is GS 4977. In some embodiments, the ASK1 inhibitor is seleonsertib (GS-4997).

In some embodiments, the one or more additional therapeutic agents are independently selected from acetylsalicylic acid, tiaprolide, aramchol, atorvastatin, BLX-1002, cenicriviroc, coleptoprost, colesevelam, enricharone, enalapril, GR-MD-02, hydrochlorothiazide, ethyl eicosapentaenoate (ethyl eicosapentaenoic acid), IMM-124E, KD-025, linagliptin, liraglutide, cysteamine, MGL-3196, obeticholic acid, oxisoxi, peg-iloleukin, pioglitazone, PX-102, remogliflozin etabonate, SHP-626, solithromycin, tylukast, TRX-318, ursodeoxycholic acid, and VBY-376.

In some embodiments, one of the one or more additional therapeutic agents is acetylsalicylic acid. In some embodiments, one of the one or more additional therapeutic agents is tipader. In some embodiments, one of the one or more additional therapeutic agents is aramchol. In some embodiments, one of the one or more additional therapeutic agents is atorvastatin. In some embodiments, one of the one or more additional therapeutic agents is BLX-1002. In some embodiments, one of the one or more additional therapeutic agents is ceriviroc. In some embodiments, one of the one or more additional therapeutic agents is a copepodone. In some embodiments, one of the one or more additional therapeutic agents is colesevelam. In some embodiments, one of the one or more additional therapeutic agents is enrichlorose. In some embodiments, one of the one or more additional therapeutic agents is enalapril. In some embodiments, one of the one or more additional therapeutic agents is GR-MD-02. In some embodiments, one of the one or more other therapeutic agents is hydrochlorothiazide. In some embodiments, one of the one or more additional therapeutic agents is ethyl eicosapentaenoate (ethyl eicosapentaenoate). In some embodiments, one of the one or more additional therapeutic agents is IMM-124E. In some embodiments, one of the one or more additional therapeutic agents is KD-025. In some embodiments, one of the one or more additional therapeutic agents is linagliptin. In some embodiments, one of the one or more additional therapeutic agents is liraglutide. In some embodiments, one of the one or more other therapeutic agents is cysteamine. In some embodiments, one of the one or more additional therapeutic agents is MGL-3196. In some embodiments, one of the one or more additional therapeutic agents is obeticholic acid. In some embodiments, one of the one or more additional therapeutic agents is orlistat. In some embodiments, one of the one or more additional therapeutic agents is a peg-ilointerleukin. In some embodiments, one of the one or more additional therapeutic agents is pioglitazone. In some embodiments, one of the one or more additional therapeutic agents is PX-102. In some embodiments, one of the one or more additional therapeutic agents is. In some embodiments, one of the one or more additional therapeutic agents is remogliflozin etabonate. In some embodiments, one of the one or more additional therapeutic agents is SHP-626. In some embodiments, one of the one or more additional therapeutic agents is solithromycin. In some embodiments, one of the one or more additional therapeutic agents is telukast. In some embodiments, one of the one or more additional therapeutic agents is TRX-318. In some embodiments, one of the one or more other therapeutic agents is ursodeoxycholic acid. In some embodiments, one of the one or more additional therapeutic agents is VBY-376.

In some embodiments, at least one of the one or more additional therapeutic agents is an anti-diabetic agent. In some embodiments, the composition is prepared byThe antidiabetic agent is adenosine A₁Receptor agonists (e.g., adenosine, CCPA, CVT-3619, GR-190718), adenosine A₂receptor antagonists (eltromycin, SCH-58261), aldose reductase inhibitors, α -amylase inhibitors (e.g., amylin, treastatin, AL-3688), α -glucosidase inhibitors (e.g., acarbose, canaglibose, diphosine, ethoglidate, miglitol, pradimicin-Q, sapindocin (sarbostatin), voglibose), amylin analogs (e.g., AC164209 and pramlintide), AMPK activators, β -adrenergic agonists (e.g., amibegron (amibegron), AZ 40140, CL-316,243, KRP-204, L-742,791, L-796,568, LY-368,842, melaleuprolide-377,604, melaleuprolide, Ro40-2148, soraferon, SWR-0342SA), beta-ketoacyl-acylprotein inhibitors, biguanides (e.g., metformin, palmatin-58261), glucagon receptor agonists (e.g., meglitinidase receptor agonists), glucagon receptor agonists (e.g., ATG-receptor antagonists, GLP-receptor agonists) (e.g., AGK-GCK-III), GLE-GCK-receptor agonists (e.g., AGP-GCK-102, GLP-receptor antagonists, GLP-102, GLP-receptor agonists (e.g., AGP-GCK-K-GCK-102, GLP-antagonist such as AGP-antagonist, GLP-5, GLP-antagonist such as, GLP-AGP-antagonist (e.g., AGP-AGG.g., AGP-7, AGK-AGP-NO-AGK-NO-7, AGK-NO-7, AGK receptor antagonist, GLP-antagonist, AGK receptor antagonist, AGK-antagonist (e.g., AGK-antagonist, AGP-NO-5, AGP-antagonist, AGK-5, AGK-antagonist, AGP-antagonist, AGK-5, AGP-5, GLP-antagonist, AGP-antagonist, AGK-AGP-antagonist, GLP-antagonist (e.g.g.g., AGP-antagonist, AGP-antagonist (AGP-AGK-antagonist, AGK-antagonist (e.g.g.g., AGK-AGGLE) and/GPT-antagonist (AGK-antagonist, AGK-AGK antagonistAgents (e.g., CC-359), kappa opioid receptor modulators, LY3084077, Kvl.3 inhibitors (e.g., ChTX, clofazimine, WIN-173173), MAP4K4 inhibitors, MC₁Or MC₄agonists (e.g., alfacatide, BMS-470539, brefelast (brefelanotide), melanotan II, PF-00446687, PL-6983, setmelanotide and THIQ), meglitinides (e.g., repaglinide, nateglinide, mitiglinide), mineralocorticoid receptor inhibitors, monoacylglycerol O-acyltransferase inhibitors, NF- κ B inhibitors, nicotinic acid receptor (HM74A) activators, PDE-10 inhibitors, PDHK2 inhibitors, PDHK4 inhibitors, PKC (including PKC- α, PKC- β and PKC- γ) inhibitors, PTP1 inhibitors (e.g., quinine (trodurine)), retinol binding protein 4 inhibitors, serine palmitoyltransferase inhibitors, SGLT1 inhibitors (e.g., GSK1614235), SIRT-1 inhibitors (e.g., resveratrol, GSK 5840, GSK184072 inhibitors), somatostatin receptor inhibitors, somatostatin agonists (e.g., acetohexamide, procarydride agonists, pioglitazone, glitazone, vaniglitazone, vanilloid receptor agonists (e), glipizide, glitazone), glitazone, vanilloid receptor agonists (e.g., vanilloid receptor agonists (e.g., vanilloid receptor agonist, vanilloid receptor agonist.

in some embodiments, the anti-obesity agent is an apoB-MTP inhibitor (e.g., dirlotape, JTT130, SLX4090, usiptade), β 3-adrenergic agonist (e.g., amibegron, AZ-40140, CL-316,243, KRP-204, L-742,791, L-796,568, LY-368,842, LY-377,604, mirabegron, Ro40-2148, solabegron, SWR-0342SA), a bombesin receptor agonist, a BRS3 modulator, a CB1 receptor antagonist or inverse agonist, CCK_AAgonists, ciliary neurotrophic factor (CNTF) or the likeSubstances (e.g. axokine, NT-501), Contrave^TM(bupropion/naltrexone), dopamine receptor agonists (e.g., bromocriptine), 11 β -hydroxysteroid dehydrogenase (11 β -HSD1) inhibitors, empathic^TM(pramlintide/metreleptin), 5-HT_2CAgonists (e.g., lorcaserin), galanin antagonists, ghrelin (ghrelin) agonists or antagonists, GLP1 agonists (e.g., albiglutide, dolabrupine, exenatide, liraglutide, lixisenatide, taslutamide), mixed glucagon receptor/GLP-1 agonists (e.g., MAR-701, ZP2929), H3 antagonists or inverse agonists, human hamster related protein (AGRP) inhibitors, leptin or analogs thereof (e.g., metreleptin), lipase inhibitors (e.g., tetrahydrolipstatin), MC₁Or MC₄Agonists (e.g., alfacatide, BMS-470539, bramer langerhan, melantan II, PF-00446687, PL-6983, setmelanotide, and THIQ), melanocyte stimulating hormone or analogs thereof, MetAp2 inhibitors (e.g., ZGN-433), monoamine reuptake inhibitors (e.g., bupropion, sibutramine, phentermine, tesofensin), neurointerleukin U receptor agonists, NPY antagonists (e.g., Weilibir), opioid receptor antagonists (e.g., naltrexone), orexin receptor antagonists (e.g., amorolene, lembolexant, SB-334,867, SB-408,124, SB-649,868, suvorexane), oxyntomodulin or analogs thereof, PYY or analogs thereof (e.g., PYY)_1-36、PYY_3-36)、Qsymia^TM(phentermine/topiramate), a RXR- α modulator, a stearoyl-CoA desaturase (SCD-1) inhibitor, or a sympathomimetic agent.

In some embodiments, at least one of the one or more additional therapeutic agents is a lipid-lowering agent. In some embodiments, the lipid-lowering agent is an acyl-CoA cholesterol acyltransferase (ACAT) inhibitor, a bile acid resorption inhibitor, a Cholesteryl Ester Transfer Protein (CETP) inhibitor, a 5-LOX inhibitor (e.g., BAY X1005), a FLAP inhibitor (e.g., AM-679), an HMG CoA synthase inhibitor, a lipoprotein synthesis inhibitor, a low density lipoprotein receptor inducer, an LXR receptor modulator, a microsomal triglyceride transporter inhibitor, niacin, a platelet aggregation inhibitor, a renin-angiotensin system inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, or a triglyceride synthesis inhibitor.

In some embodiments, at least one of the one or more additional therapeutic agents is a drug for treating a metabolic disease. In some embodiments, the agent for treating a metabolic disease is an ABC transporter activator, ACT-434964(Actelion), an ANG-5 inhibitor, an angiotensin II antagonist (e.g., MC4262), CCX-872, DUR-928(Durect), ESP41091, F-652

(Generon), FGF21 agonists (e.g., BMS-986036), methylpyrazole (Raptor), FXR agonists, FXR/TGR5 dual agonists (e.g., INT-767), ghrelin antagonists (e.g., TZP-301), glucosylceramide synthase inhibitors, GPR17 modulators, GPR119 agonists, IG-MD-014 (indigo), IMM-124E (Immuron), lysosomal pathway modulators (e.g., CAT5000), melanin concentrating hormone receptor 1 antagonists (e.g., KI-1361-17), MCL1 inhibitors (e.g., CMPX-1023), mTORC1 inhibitors, NaCT (e.g., 13A5) inhibitors, NHE3 inhibitors (e.g., RDX-011, tenatoporan), NP (Neurartus), PBI-4050 (Proic), protein homeostasis modulators (e.g., PTI-130, PTI-C-1811), PHrmacoene 8288 (SLC) 102/mPX 102/102) RG7410.RG7652, ROCK inhibitors, SBC-104(Synageva BioPharma), SPX-100(Spherix), stearoyl CoA desaturase inhibitors (e.g., CVT-12805), TRC150094(Torrent), or ZYH7(Zydus Cadila).

In some embodiments, at least one of the one or more additional therapeutic agents is a drug for the treatment of steatosis. In some embodiments, the agent for treating steatosis is an adiponectin analog (e.g., PX 811013), aramchol (Galmed), an ASK1 inhibitor (e.g., GS4977, GS4997 (also known as seleonchromene)), AZD4076(AstraZeneca), a bile acid sequestrant (e.g., obeticholic acid), BL-1060 (galved), BMS986171(Bristol-Myers Squibb), a CCR5/CCR2 antagonist (e.g., cenicriviroc), cannabidiol, CER-209(Cerenis), a cysteamine analog (e.g., RP-103, RP-104), DS102(DS Biopharma), EGS21(Enzo), elafibanobranor (Genfit), Enlicarban (Idun), ethacrylonin (ethicone), or a pharmaceutically acceptable salt thereofEicosapentaenoic acid (Mochida), FXR agonists, GPBAR1 agonists (e.g., RDX009), GR-MD-02(Galectin Therapeutics), leucine/sildenafil/metformin (NuSirt), LCQ908(Novartis), LJN452(Novartis), LOXL2 inhibitors (e.g., octazumab), MAT-8800(Matinas), MB-10866 (Metabass), miR-103/107 inhibitors (e.g., RG-125), MK-4074 (Merck)&Co.), nalmefene (TaiwanJ), nivocasan (Gilead), NGM-282(NGM Biopharmaceuticals), omega-3 carboxylic acids or mixtures thereof (e.g., Epanova)^TM) PX-102(Phenex), PX-104(Phenex), regorazin etabonate (Kissei), Saroglipta (Zydus-Cadila), SAR-548304(sanofi-aventis), tylukast (Kyorin), ursodeoxycholic acid, VK2809(Viking), or XL335 (Exelixis).

In some embodiments, the additional therapeutic agent is selexostat, a san FXR agonist, or a combination thereof.

In some embodiments, at least one of the one or more additional therapeutic agents is a drug for treating inflammation. In some embodiments, the medicament for treating inflammation reduces T_hin some embodiments, the agent for treating inflammation is a caspase inhibitor (e.g., enrikagan), a TGF- β inhibitor, an IL-1 β inhibitor, an IL-6 inhibitor, an IL-17a inhibitor, an IL-17F inhibitor, an IL-21 inhibitor, an IL-23 inhibitor (e.g., guselkumab), an IMM-124E, ROR γ t inhibitor (e.g., JTE-151), a ROR α inhibitor, solithromycin (Cempra), or a vascular adhesion protein-1 inhibitor (e.g., PXS-4728A).

In some embodiments, at least one of the one or more additional therapeutic agents is a drug for treating fibrosis. In some embodiments, the agent for treating fibrosis is cenicriviroc (Tobira/Takeda), CNX-014/023/024/025(Connexios), an endothelin antagonist (e.g., a192621, ambrisentan, atracentan, bosentan, BQ-123, BQ-788, macitentan, sitaxentan, tezosentan, zipontentan), etanercept, evitar (AdeTherapeutics), a fibroblast growth factor inhibitor, galectin-3 inhibitor, imatinib, IVA337(Inventiva), N-acetyl cysteine, nintedanib, pirfenidone, RG6069(Roche), SP20102 (saruz), tafelast (Kyorin), or XOMA 089 (XOMA).

in some embodiments, the methods of treatment provided herein further comprise administering to the patient an ACC inhibitor, e.g., compound 1 or compound 2, in combination with a PPAR α agonist or fish oil, and optionally an additional therapeutic agent selected from selectrostat, an FXR agonist, or a combination thereof.

in some aspects, provided herein is a method of treating, stabilizing or reducing the severity or progression of nonalcoholic steatohepatitis (NASH), wherein the method comprises administering to a patient in need thereof compound 1 in combination with a PPAR α agonist or fish oil, and optionally an additional therapeutic agent selected from spirochromene, an FXR agonist, or a combination thereof.

in some aspects, provided herein is a method of treating, stabilizing or reducing the severity or progression of nonalcoholic steatohepatitis (NASH), wherein the method comprises administering to a patient in need thereof compound 2 in combination with a PPAR α agonist or fish oil, and optionally an additional therapeutic agent selected from spirochromene, an FXR agonist, or a combination thereof.

in some aspects, provided herein is a method of treating, stabilizing or reducing the severity or progression of nonalcoholic steatohepatitis (NASH), wherein the method comprises administering to a patient in need thereof 20mg of compound 1 in combination with a PPAR α agonist or fish oil, and optionally an additional therapeutic agent selected from spirochromene, an FXR agonist, or a combination thereof.

in some aspects, provided herein is a method of treating, stabilizing or reducing the severity or progression of nonalcoholic steatohepatitis (NASH), wherein the method comprises administering to a patient in need thereof 20mg of compound 2 in combination with a PPAR α agonist or fish oil, and optionally an additional therapeutic agent selected from spirochromene, an FXR agonist, or a combination thereof.

In some aspects, provided herein are methods of treating, stabilizing, or reducing the severity or progression of nonalcoholic steatohepatitis (NASH), wherein:

the method comprises administering to a patient in need thereof about 20mg of compound 1 in combination with a PPAR α agonist or fish oil, and optionally an additional therapeutic agent selected from selexostat, an FXR agonist, or a combination thereof, and

the patient had a serum triglyceride level <250mg/dL prior to administration.

the method comprises administering to a patient in need thereof about 20mg of compound 2 in combination with a PPAR α agonist or fish oil, and optionally an additional therapeutic agent selected from spirochromene, an FXR agonist, or a combination thereof, and

the patient had a serum triglyceride level <250mg/dL prior to administration.

the method comprises administering to a patient in need thereof about 20mg of Compound 1 in combination with a PPAR α agonist or fish oil, and optionally an additional therapeutic agent selected from spirochromene, an FXR agonist, or a combination thereof,

the PPAR α agonist is fenofibrate, bezafibrate, elafinibrane or saroglitazar, and

the patient had a serum triglyceride level <250mg/dL prior to administration of compound 1 in combination with a PPAR α agonist or fish oil.

the method comprises administering to a patient in need thereof about 20mg of Compound 2 in combination with a PPAR α agonist or fish oil, and optionally an additional therapeutic agent selected from spirochromene, an FXR agonist, or a combination thereof,

the patient had a serum triglyceride level <250mg/dL prior to administration of compound 2 in combination with a PPAR α agonist or fish oil.

the patient is administered a PPAR α agonist or fish oil prior to administration of compound 1 (optionally in combination with a PPAR α agonist or fish oil).

the patient is administered a PPAR α agonist or fish oil prior to administration of compound 2 (optionally in combination with a PPAR α agonist or fish oil).

Combined administration

as described herein, the term "combination" with respect to the administration of an ACC inhibitor, e.g., compound 1 or compound 2, a PPAR α agonist or fish oil, and optionally one or more other therapeutic agents, means that the ACC inhibitor, e.g., compound 1 or compound 2, a PPAR α agonist or fish oil, and optionally one or more therapeutic agents, can each be administered to a patient in any order (i.e., simultaneously or sequentially) or together in a single composition, formulation, or unit dosage form.

it is understood that an ACC inhibitor, e.g., compound 1 or compound 2, a PPAR α agonist or fish oil, and optionally one or more other therapeutic agents, may be administered in any order, either on the same day or on different days, according to a suitable dosing regimen.

in some embodiments, administration of the PPAR α agonist or fish oil begins before the start of administration of the ACC inhibitor, e.g., compound 1 or compound 2, for a period of time (e.g., at least one day, three days, one week, two weeks, or one month), and optionally continues for at least a portion of the dosing period of the ACC inhibitor, e.g., compound 1 or compound 2. in some embodiments, administration of the PPAR α agonist or fish oil begins on the same day as the start of administration of the ACC inhibitor, e.g., compound 1 or compound 2. in some embodiments, after the start of administration of the ACC inhibitor, e.g., compound 1 or compound 2, the inhibitor, e.g., compound 1 or compound 2, is administered with the PPAR α agonist or fish oil for at least a period of time (e.g., at least one day, three days, one week, two weeks, or one month).

administration of PPAR α agonists or other therapeutic agents

in some embodiments, the amount of PPAR α agonist or optional additional therapeutic agent administered is from about 0.1 mg/day to about 1200 mg/day, in some embodiments, the amount of PPAR α agonist or one or more optional additional drugs administered is from 1 mg/day to about 100 mg/day, from about 10 mg/day to about 1200 mg/day, from about 10 mg/day to about 100 mg/day, from about 100 mg/day to about 1200 mg/day, from about 400 mg/day to about 1200 mg/day, from about 600 mg/day to about 1200 mg/day, from about 400 mg/day to about 800 mg/day, or from about 600 mg/day to about 800 mg/day.

in some embodiments, the total daily dose of each of the PPAR α agonists or one or more other therapeutic agents is selected from about 5mg, about 10mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 280mg, about 290mg, about 500mg, about 800mg, about 500mg, about 800mg, about 500mg, about 800 mg.

in some embodiments, the total daily dose of each of the PPAR α agonists or the one or more other therapeutic agents is independently from about 5mg to about 3000mg, from about 5mg to about 1000mg, from about 5mg to about 500mg, from about 5mg to about 100mg, from about 10mg to about 3000mg, from about 10mg to about 2000mg, from about 10mg to about 1000mg, from about 20mg to about 1000mg, from about 30mg to about 750mg, from about 30mg to about 500mg, from about 30mg to about 250mg, from about 30mg to about 100mg, from about 50mg to about 500mg, or from about 50mg to about 100 mg.

Unit dosage forms of other therapeutic agents

in some embodiments, each of the PPAR α agonist and the one or more optional additional therapeutic agents is administered in a unit dosage formulation comprising from about 0.1mg to about 2000mg, from about 1mg to 200mg, from about 35mg to about 1400mg, from about 125mg to about 1000mg, from about 250mg to about 1000mg, or from about 500mg to about 1000mg of the PPAR α agonist or therapeutic agent.

in some embodiments, provided herein are unit dose formulations comprising about 0.1mg, 0.25mg, 0.5mg, 1mg, 5mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg, 100mg, 125mg, 150mg, 200mg, 250mg, 300mg, 400mg, 600mg, or 800mg of a PPAR α agonist or other therapeutic agent.

in some embodiments, provided herein are unit dosage formulations comprising 0.1mg, 0.25mg, 0.5mg, 1mg, 2.5mg, 5mg, 10mg, 15mg, 20mg, 30mg, 35mg, 50mg, 70mg, 100mg, 125mg, 140mg, 175mg, 200mg, 250mg, 280mg, 350mg, 500mg, 560mg, 700mg, 750mg, 1000mg, or 1400mg of a PPAR α agonist or other therapeutic agent.

administration of PPAR α agonists or fish oils or other therapeutic agents

in some embodiments, provided methods comprise administering a pharmaceutically acceptable composition comprising a PPAR α agonist or fish oil or one or more other therapeutic agents once, twice, three times, or four times daily.

in some embodiments, a pharmaceutically acceptable composition comprising a PPAR α agonist or fish oil or one or more other therapeutic agents is administered once daily ("QD").

in some embodiments, twice daily administration refers to administration of the compound or composition as "BID", or two equal doses given at two different times of the day.

in some embodiments, a pharmaceutically acceptable composition comprising a PPAR α agonist or fish oil or one or more other therapeutic agents is administered "TID", or three equal doses are given at three different times of the day.

in some embodiments, a pharmaceutically acceptable composition comprising a PPAR α agonist or fish oil or one or more other therapeutic agents is administered four times per day, hi some embodiments, a pharmaceutically acceptable composition comprising a PPAR α agonist or fish oil or one or more other therapeutic agents is administered as a "QID," or four equal doses are given at four different times of the day.

in some embodiments, the PPAR α agonist or fish oil or other therapeutic agent is administered to the patient under fasting conditions and the total daily dose is any of the doses above and contemplated herein.

in some embodiments, the PPAR α agonist or fish oil or other therapeutic agent is administered to the patient under fed conditions and the total daily dose is any of the doses above and contemplated herein.

in some embodiments, the PPAR α agonist or fish oil or other therapeutic agent is administered orally.

the PPAR α agonist or therapeutic agent may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin.

pharmaceutically acceptable compositions of compound 1 or compound 2 and a PPAR α agonist

in some embodiments, the present invention provides a pharmaceutically acceptable composition comprising compound 1 or compound 2, or a pharmaceutically acceptable composition of a PPAR α agonist, for use in the methods described herein.

Exemplary such pharmaceutically acceptable compositions are further described below and herein.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the ACC inhibitor and/or one or more other therapeutic agents, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable carriers and solvents that may be employed are water, ringer's solution, U.S. p. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as oleic acid, may be used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

in order to prolong the effect of compound 1 or compound 2 and/or a PPAR α agonist, it is often desirable to delay absorption following subcutaneous or intramuscular injection this may be achieved by using a liquid suspension of a crystalline or amorphous material which is poorly water soluble, the rate of absorption depending on its rate of dissolution which in turn may depend on crystal size and crystal form.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, for example sodium citrate or dicalcium phosphate, and/or a) fillers or extenders, for example starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) wetting agents, for example glycerol, d) disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retarders, for example paraffin, f) absorption accelerators, for example quaternary ammonium compounds, g) wetting agents, for example cetyl alcohol and glycerol monostearate, h) absorbents, for example kaolin and bentonite, and i) lubricants, for example talc, calcium stearate, Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft or hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents, or may be of a composition that they release the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

solid dosage forms of compound 1 or compound 2 and/or the PPAR α agonist may also be in microencapsulated form, containing one or more of the above excipients, tablets, lozenges, capsules, pills and granules may be prepared using coatings and shells, such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulation art in such solid dosage forms, compound 1 or compound 2 and/or the PPAR α agonist may be mixed with at least one inert diluent, such as sucrose, lactose or starch.

dosage forms for topical or transdermal administration of compound 1 or compound 2 and/or a PPAR α agonist include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as required ophthalmic formulations, ear drops and eye drops are also encompassed within the scope of the invention.

according to one embodiment, the present invention relates to a method of inhibiting de novo fatty acid synthesis in a biological sample comprising the step of contacting said biological sample with compound 1 or compound 2 and/or a PPAR α agonist.

according to one embodiment, the present invention relates to a method of increasing fatty acid oxidation in a biological sample comprising the step of contacting said biological sample with compound 1 or compound 2 and/or a PPAR α agonist.

The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

Example 1

Use of Compound 1 in a phase 2, randomized, placebo-controlled trial in NASH patients

The method comprises the following steps: in this double-blind, placebo-controlled trial, 126 non-cirrhosis subjects with NASH, diagnosed noninvasively by MRI Proton Density Fat Fraction (PDFF) ≥ 8% and MR elastography (MRE) liver stiffness ≥ 2.5kPa or historical liver biopsy consistent with NASH and grade 1-3 fibrosis, were orally randomized to receive 20mg of Compound 1, 5mg of Compound 1 or placebo QD once a day at 2:2:1 for 12 weeks (W12). MRI-PDFF and MRE and fibriscan and fibrotic serum markers read in the set were measured at baseline and W12. In some subjects, transient elastography techniques are used: (

Echosens, Paris, France) evaluated liver hardness and liver fat content at baseline (i.e., week 0) and week 12 (by controlled decay parameters)，CAP)。

In addition to standard lipid tests (serum triglycerides ("TG"), total cholesterol ("TC"), low density lipoprotein cholesterol ("LDL-C") and high density lipoprotein cholesterol ("HDL-C"), nuclear magnetic resonance spectroscopy (NMR)

LabCorp) lipoproteins were measured in fasting serum samples at baseline ("BL"), week 1 (W1), week 4 (W4), and W12. Compound 1 treated subjects were evaluated for changes from baseline using the Wilcoxon signed rank test (Wilcoxon sign-rank test) and using the Wilcoxon rank-sum test versus placebo, both adjusted using Bonferroni.

Acylcarnitine species measurements were performed using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS; Waters Acquity UHPLC, Waters corporation, Milford, MAUSA) and a hybrid quadrupole-orbitrap mass spectrometer (Q-active Thermo fischer scientific, Waltham, MA, USA) platform in known electrospray ionization positive and negative modes.

Results (MRI-PDFF and MRE): the majority of subjects were female (65%) and diabetic (60%); median MRI-PDFF and MRE-hardness at baseline were 14.4% (IQR 11.1-19.0) and 3.43kPa (2.96-4.20), respectively; the MRE of 40% of subjects was >3.64kPa, consistent with late (. gtoreq.F 3) fibrosis. At W12, 20mg compound 1 resulted in a statistically and clinically significant reduction in MRI-PDFF compared to placebo; the difference between 5mg compound 1 and placebo was not statistically significant (table 1). At W12, a reduction of MRI-PDFF of > 30% was observed in 48% of subjects treated with 20mg of compound 1 (p 0.004 compared to placebo), 23% of subjects treated with 5mg of compound 1 (p 0.433 compared to placebo) and 15% of subjects treated with placebo.

In some subjects, hepatic steatosis is measured by CAP. A dose-dependent decrease in CAP was observed in compound 1 treated patients, in parallel with changes in MRI-PDFF, but CAP differences were not statistically significant (data not shown). The difference in CAP change between the patients treated with Compound 1 and those taking placebo was most pronounced when measured using the XL probe and the M probe.

The change in liver hardness measured by MRE was not different between groups. However, TIMP-1 serum levels were significantly reduced in subjects treated with 20mg compound 1 (table 1); TIMP-1 changes were associated with changes in PIII-NP (r ═ 0.47; p ═ 0.001) and hyaluronic acid (r ═ 0.62; p < 0.001). Dose-dependent but not statistically significant reductions in serum ALT, liver hardness (by FibroScan) and PIII-NP were also observed. Compound 1 is generally well tolerated. Liver stiffness changes (by Fibroscan) appear to be dependent on the type of probe used, as well as consistent use of the same type of probe over time. Using the M probe, no difference in liver hardness was observed from baseline to week 12 between treatment groups. In patients measured using XL probes, a statistically significant decrease in liver hardness was observed in compound 1 treated patients compared to placebo. Specifically, the consistent use of a median (IQR) relative change from baseline to week 12 of-7.2% (-32.6,7.8) in patients treated with 120mg compound (p ═ 0.04 compared to placebo), of-3.6% (-23.8,8.2) in patients treated with 15mg compound (p ═ 0.02 compared to placebo), and of + 30.6% (4.5, 63.8)/the same probe between measurements was also associated with a significant decrease in liver stiffness in the compound 1 treated group compared to placebo.

The median relative change (IQR) results for ALT, AST, GGT, ALP, TIMP-1, PIII-NP and HA at W12 are also summarized in FIG. 1. The p-values reported in figure 1 were used to compare compound 1 with placebo by the Wilcoxon rank-sum test. The median relative reduction of ALT, TIMP-1 and PIII-NP was greater in patients receiving Compound 1 at any dose than in patients receiving placebo. TIMP-1 was statistically significant (p ═ 0.022) between patients receiving 20mg of compound 1 and placebo (fig. 1). Median alkaline phosphatase was increased by 9% in patients receiving 20mg of compound 1 (p <0.001 compared to placebo), but remained unchanged or decreased in patients receiving 5mg of compound 1 and placebo, respectively. Other liver biochemical tests and changes in composite ELF scores were not significantly different in each treatment group. 33 patients exhibiting at least a 30% relative reduction from baseline of MRI-PDFF also showed reduced liver biochemistry (ALT, AST, GGT) and ELF scores and their components compared to PDFF-non-responders (n ═ 60) (fig. 3).

in contrast to the 20mg compound 1 treatment group that exhibited a PDFF response, where a variety of long and medium chain acylcarnitines (surrogate markers of increased β oxidation of fatty acids) were significantly reduced prior to administration of the next daily dose (about 24 hours) (table 3), patients in the 5mg compound 1 or placebo group showed minimal acylcarnitines change when compared according to PDFF response.

Results (lipid parameters): median age was 56 years, 67% women, 60% had diabetes, and 45% used lipid lowering therapy at BL (39% statins, 4.8% fibrates, 17% others). At W12, median relative changes in Triglyceride (TG) were observed to be + 11%, + 13%, and-4% in subjects treated with 20mg compound 1, 5mg compound 1, and placebo. An asymptomatic increase in grade 3 or 4 TG (>500mg/dL) was observed in 16 subjects taking 20mg (n ═ 7) or 5mg (n ═ 9) of compound 1. Of the 16 subjects, 4 subjects responded to fibrate or fish oil treatment, and 7 of the remaining 12 subjects resolved without treatment with compound 1 or discontinuation of treatment. The primary factor associated with a grade 3 or 4 TG increase was a baseline TG level >250mg/dL (p < 0.001).

TG rise of subjects taking compound 1 peaked at W1 and then decreased (table 2). At W12, an increase in median (IQR) TG of 14mg/dL (-6,72) was observed in compound 1 treated subjects (p 0.14) compared to a 5.5mg/dL (-24,26) decrease in placebo. The statistically significant increase in Very Low Density Lipoprotein (VLDL) particles and VLDL-TG at W1 was no longer significant at W12. Changes in HDL-C, TC and LDL-C from baseline in W12 were not significant in subjects treated with Compound 1, but TC and LDL-C were reduced in placebo. No significant change in total HDL or total LDL particles was observed in subjects taking compound 1. There was also no significant change in glucose, insulin or HbAlc with 20mg compound 1 or 5mg compound 1 compared to placebo.

And (4) conclusion: in this randomized, placebo-controlled study, 12-week therapy with an oral ACC inhibitor targeting the liver (20mg compound 1, QD) was safer and resulted in significant improvement in hepatic steatosis and selected fibrosis markers in NASH patients. In addition, it is expected that elevated TG in NASH patients treated with 20mg compound 1 per day may be associated with a transient increase in hepatic release of VLDL particles. Despite the increased serum TG concentrations, HDL and LDL particles were not significantly altered.

TABLE 1 relative (%) change in imaging, ALT and serum fibrosis markers at W12

Unless indicated, all data are median relative (%) change from baseline. The n value in each table header refers to the total number of subjects in each treatment group; the n values shown within the cells describe the number of subjects for the data shown.

Table 2: lipid parameters in subjects treated with 20mg of Compound 1 daily for 12 weeks

The data is the median value (IQR).

HDL-P, total HDL particles; LDL-P, total LDL particles; VLDL-P, total VLDL particles; VLDL-TG, VLDL triglycerides.

P <0.05 compared to BL.

Comparison of the change from BL, p, compared to placebo<0.05。

Table 3: acylcarnitine substances in patients treated with 20mg of compound 1

Example 2a

Compound 2 and fenofibrate: 14-day oral and dietary pharmacological study using a fast food diet model of male C57B1/6 mouse fatty liver

purpose the purpose of this study was to evaluate the effect of compound 2 on deuterium incorporation in plasma and liver TG and liver molecular biology after 10 to 14 days of compound 2 administration in a fast food diet-induced model of mouse non-alcoholic steatosis the mice recruited to this study were fed a fast food diet for approximately 9 months before the study began the primary endpoints were deuterium incorporation in plasma TG, total plasma TG and PPAR α, Liver X Receptor (LXR) and chromatin Immunoprecipitation (IP) of liver retinoic acid X receptor α (RXR α).

Statement of animal care and use: all procedures in this protocol followed Animal Welfare (Animal Welfare Act), Laboratory Animal Care and instructions for Use (Guide for the Care and Use of Laboratory animals), and Laboratory Animal Welfare Office (Office of Laboratory Animal Welfare). From the perspective of the sponsor and the research leader, the research does not need to repeat any of the previous works, and no other model can meet the research requirements.

Test details:

● NA is not suitable

● vehicle: 0.5% sodium carboxymethylcellulose (medium viscosity), 1% ethanol, 98.5% 50mM tris buffer, pH 8. + -. 0.5, in reverse osmosis water (or equivalent)

● Compound 2(Cmpd 2): in vehicle solution (pH: 7.5 to 8.5).

● fenofibrate: 0.1% ground in diet.

● snack and standard diet mice were randomized to treatment groups based on body weight collected on day 1

● fructose/glucose water

● Pre-administration phase

● animals 1 to 98: fructose/glucose water

● animals 99 to 108: tap water is obtained at will

● administration phase

● sets 1 to 4: fructose/glucose water

● group 5: tap water is obtained at will

●²H₂O (deuterium oxide-heavy water):

●²H₂o rapid concentrated injection: each animal in groups 1-3 was administered 25mL/kg by Intraperitoneal (IP) injection on day 10²H₂And O. If applicable, after Compound 2²H₂O。

● in drinking water²H₂O: administration to each animal in groups 1 to 3 immediately after IP injection by the study leader on day 10²H₂O。

● Whole blood samples were collected during the experiment. The liver was observed and tissue samples were collected. Animals were fasted for approximately 4 to 6 hours prior to each individual blood draw and scheduled sacrifice.

Example 2b

Compound 2 and fenofibrate administered once daily in feed (chow): 14-day pharmacological study using a fast food diet model of male C57B1/6 mouse fatty liver

the objective of this study was to evaluate the effect of compound 2(10mg/kg QD) or fenofibrate (0.1% administered as feed) or a combination thereof on plasma and hepatic TG and hepatic molecular biology after 10 to 14 days of oral administration of compound 2(10mg/kg QD) or fenofibrate (0.1% administered as feed) or combination thereof in mice fed a high fat, cholesterol and fructose diet (fast food diet, FFD). before the study began, mice enrolled in this study were fed a fast food diet for approximately 9 months.

Statement of animal care and use: all procedures in this protocol followed animal welfare, laboratory animal care and instructions for use, and laboratory animal welfare offices. From the perspective of the sponsor and the research leader, the research does not need to repeat any of the previous works, and no other model can meet the research requirements.

Table 4: details of testing

● NA is not suitable

● Compound 2(Cmpd 2): in vehicle solution (pH: 7.5 to 8.5).

● fenofibrate: 0.1% ground in diet.

● fructose/glucose water

● Pre-administration phase

● animals 1 to 80: fructose/glucose water

● administration phase

● all groups: fructose/glucose water

● Whole blood samples were collected during the survival of the study and livers were collected at the end. Animals were fasted for approximately 4 to 6 hours prior to each separate blood draw and scheduled sacrifice.

two weeks after administration of compound 2 in this model, plasma triglycerides were significantly increased by 15% relative to vehicle treated animals, whereas co-administration of fenofibrate in feed with compound 2 resulted in a significant decrease in plasma triglycerides relative to compound 2 treated and vehicle control groups (see figure 4). treatment with compound 2 was associated with increased target gene expression, and the addition of fenofibrate was associated with a decrease in LXR α and SREBP1 target gene expression (figure 6A-B). it is thus expected that ACC inhibitor, compound 2 "(C2") -mediated hypertriglyceridemia may require LXR α/SREBP1 activation and PPAR α reduction.

in conclusion, the data demonstrate that co-administration of compound 2 with a PPAR α agonist improves plasma hypertriglyceridemia induced by ACC inhibition.

Example 3

Compound 1 in patients with compensated cirrhosis by NASH

The method comprises the following steps: in the proof-of-concept study, 10 patients were affected with suspected compensatory cirrhosis (Child-Turcotte-Pugh [ CTPJ-A) by NASH (by biopsy, liver stiffness (by magnetic resonance elastography [ MRE ])]> 4.67 kPa or transient elastography techniques > 14.0kPa or Fibrotest > 0.75) for 12 weeks per day. Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and MRE and fibrotic serum markers read centrally were measured at Baseline (BL), week 4 (W4) and week 12 (W12). For DNL assay, three administrations of heavy water per day before baseline, W4 and W12: (²H₂O,35mL) and continued for one week of circulation. Deuterium incorporation in palmitate was measured by GC/MS in fasting plasma samples and inhibition thereof by hepatic DNL and compound 1 was calculated using mass isotope distribution analysis.

As a result: a statistically significant reduction in hepatic PDFF (median: 9.2 vs. 4.6%; P ═ 0.004) and serum ALT (46 vs. 32U/L; P ═ 0.008; fig. 2) was observed after 12 weeks of compound 1 treatment compared to BL. PDFF decreased significantly at W4. A relative reduction of 30% or more was seen in W4 in 5 subjects (50%) and in W12 in 7 subjects (70%). No significant changes in MRE-hardness or serum fibrosis markers were observed. The PDFF reduction was associated with changes in ALT, ELF score, and PIII-NP. Compound 1 is well tolerated; and no subjects prematurely discontinued study medication. The median (IQR) 147mg/dL (105,231) on fasting triglycerides BL increased to 159mg/dL (142,248) of W12 (P ═ 0.008), but the other lipid parameters were unchanged. One subject had asymptomatic hypertriglyceridemia level 3 and responded to a fibrate therapy. Data on the effect of compound 1 on fasting liver DNL have not been published.

And (4) conclusion: in the proof-of-concept study, 12-week therapy with liver-targeted oral compound 1 was safer in subjects with compensated cirrhosis caused by NASH and was involved in association with significant improvement in hepatic steatosis and serum ALT.

Example 4

Compound 1 in a patient

10 subjects with steatosis (MRI-PDFF ≧ 10%) and F1-F3 fibrosis (MRE ≧ 2.88kPa but not cirrhosis based on FibroText <0.75, historical imaging and liver biopsy) were treated with 20mg of Compound 1 for 12 weeks.

4 of 10 subjects were taking fish oil or fenofibrate at baseline and continued to be administered concomitant medication for the duration of the study. Throughout the study, subjects were monitored for safety (adverse events, laboratory abnormalities), liver biochemistry, fibrotic serum markers (ELF and its components TIMP-1, hyaluronic acid, PIII-NP), and cell death (CK 18M 30 and M65), liver hardness (MRE), and fat (MRI-PDFF) and the effect on de novo lipogenesis was evaluated using a heavy water marker.

4 subjects were analyzed in combination with 8 subjects from the study described in example 1. The 12 subjects were taking fish oil or fibrate for at least 6 weeks in the study and included those taking fish oil or fibrate at baseline or those with graded hypertriglyceridemia and given fish oil or fibrate during the study. The results are summarized in table 6 and fig. 7.

Table 6: compound 1 and fibrate/fish oil show improved efficacy

The continuous data is a median value (IQR); shellfish/fish oil>6 weeks; patient started using fenofibrate after week 1;

only the phase 2 study is illustrated in example 1, with n ═ 6 for compound 1+ fibrate/fish oil.

as shown in table 6, nearly all imaging, liver biochemistry, fibrosis serum markers and metabolic parameter data demonstrated that the combination of compound 1 with a PPAR α agonist (fenofibrate or fish oil) improved potency compared to compound 1 alone, PIII-NP was similar in 3 treatment groups.

all monitored TG-related measurements (total TG, apolipoprotein B48 ("APOB 48"), VLDL-P, and apolipoprotein C3 ("APOC 3")) improved to less than baseline after using fenofibrate dry (fig. 8A and 8B).

Example 5

Compound 1 in NASH patients

Subjects who were not taking pre-existing fibrates or fish oils and who included F3-F4NASH fibrosis exhibiting compensated liver function, as determined by screening for noninvasive markers over 6 months and historical biopsies, were administered 20mg of compound 1 and fenofibrate at a dose strength (e.g., 145 mg). Some subjects in >250mg/dL triglycerides may be enrolled (approximately 75%), but subjects with >750mg/dL triglycerides may be excluded. Liver biochemistry (ALT, AST, GGT), fibrotic serum markers (e.g., ELF and its components), and metabolites (e.g., HBA1C, insulin, glucose, acylcarnitines) and imaging (e.g., MRI-PDFF, MRE, fibrosan) were measured at different time intervals (e.g.,

weeks

0, 4,8, 12, and 24).

Example 6

Once daily oral administration of compound 2 and fenofibrate: 15-day pharmacological study of fast food diet model using fatty liver from male C57BL/6 mice

purpose of this study the purpose of this study was to evaluate the effect of compound 2 on plasma and hepatic Triglycerides (TG) and hepatic molecular biology 15 days after oral administration ("PO") of compound 2(5mg/kg QD), fenofibrate (25mg/kg and 50mg/kg QD), or combination (compound 2(5mg/kg QD) + fenofibrate (50mg/kg QD)) in mice on a high fat, cholesterol and fructose diet (research diet FFD 12079B). about 9 months before the start of the study, mice enrolled in this study were fed FFD with hepatic gene expression and profibrotic markers (by qPCR) with primary endpoints of plasma TG, hepatic ketone bodies, plasma hepaplastin, hepatic oxidative stress and hepatic X receptor α (LXR α) and PPAR α targets.

Table 7: details of testing

● vehicle: vehicle: 25% (v/v)

PEG

200, 75% (v/v) [ 0.5% (w/v) methylcellulose A4M in purified water ].

● vehicle solution of Compound 2 (pH: 7.5 to 8.5).

● fenofibrate in vehicle solution (pH: 7.5 to 8.5).

● mice were randomized into treatment groups based on body weight collected on day 1.

● fructose/glucose water

pre-administration phase

■ animals 1 to 72 fructose/glucose water

period of administration

■ all groups fructose/glucose water

● at the end, whole blood samples and liver were collected. Animals were sacrificed 2h after dosing in ad libitum fed state.

after 215 days of compound administration in the FFD model, plasma TG was significantly increased by 29% relative to vehicle treated animals, while co-administration of fenofibrate (50mg/kg) with compound 2 significantly reduced plasma TG relative to vehicle, compound 2 and fenofibrate (50mg/kg) groups (fig. 9) treatment with compound 2 resulted in a reduction in PPAR α target gene expression, which was increased relative to compound 2 and vehicle treated groups when treated with the combination of compound 2 and fenofibrate (fig. 10A), as opposed to LXR α target gene expression increase when treated with compound 2, and the combination of compound 2 with fenofibrate (50mg/kg) normalized expression (fig. 10B) compound 2 reduced plasma ALT and AST levels, and which was further reduced when treated with the combination of fenofibrate (50mg/kg) (fig. 11A and 11B) similarly, treatment with single compound 2 could reduce liver TG and compound 2/fenofibrate combination treatment resulted in a further reduction (fig. 12A) when treated with fenofibrate (12 mg/kg) and further increased liver stress level when treated with fenofibrate (ohba) as compared to no more than the single fenofibrate 2 mg/kg) gene expression of fenofibrate (fig. 14A) and 12 mg/kg), whereas the fenofibrate (2) treatment with the combination of fenofibrate 2) had a reduced liver stress effect when treated with the single fenofibrate (2) administration of fenofibrate alone (fig. 14 mg).

the data demonstrate that co-administration of compound 2 with a PPAR α agonist improves the plasma hypertriglyceridemia induced by ACC inhibition and has greater efficacy at the steatosis and fibrosis endpoints.

Claims

1. a method of treating, stabilizing or reducing the severity or progression of nonalcoholic fatty liver disease, wherein the method comprises administering compound 1 or compound 2 in combination with a PPAR α agonist or fish oil to a patient in need thereof, wherein the PPAR α agonist is selected from the group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemafibrate, chlorofibrate, bisfibrate, omega-3 fatty acids, pilinamide, GW409544, AZ242, LY518674, NS-220, AVE8134, BMS-711939, argazazar, and moglica.

2. a method of treating, stabilizing or lessening the severity or progression of non-alcoholic fatty liver disease while reducing or eliminating the appearance of or lessening the severity of hypertriglyceridemia, wherein said method comprises administering compound 1 or compound 2 in combination with a PPAR α agonist or fish oil to a patient in need thereof.

3. The method according to claim 1 or 2 wherein the NAFLD is selected from steatosis, non-alcoholic steatohepatitis, liver fibrosis due to non-alcoholic steatohepatitis, cirrhosis due to non-alcoholic steatohepatitis and hepatocellular carcinoma due to non-alcoholic steatohepatitis.

4. a method of treating, stabilizing or reducing the severity or progression of nonalcoholic steatohepatitis, wherein the method comprises administering compound 1 or compound 2 in combination with a PPAR α agonist or fish oil to a patient in need thereof, wherein the PPAR α agonist is selected from the group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemafibrate, chlorofibrate, bisfibrate, omega-3 fatty acids, pilinamide, GW409544, AZ242, LY518674, NS-220, AVE8134, BMS-711939, argazazar, and moglica.

5. a method of treating, stabilizing or lessening the severity or progression of non-alcoholic steatohepatitis while reducing or eliminating the appearance of or lessening the severity of hypertriglyceridemia, wherein said method comprises administering compound 1 or compound 2 in combination with a PPAR α agonist or fish oil to a patient in need thereof.

6. The method according to any one of claims 1-5, wherein the patient is non-cirrhotic.

7. The method according to any one of claims 1-6, wherein the patient has grade 1 to 4 fibrosis.

8. The method according to any one of claims 1-7, wherein the patient has a magnetic resonance imaging proton density fat fraction (MRI-PDFF) at baseline of at least about 8%.

9. The method according to any one of claims 1-8, wherein the patient has a liver stiffness at baseline of at least about 2.5 kPa.

10. The method according to one of claims 1-9, wherein said patient has plasma triglyceride levels at baseline of at least about 150 mg/dL.

11. The method according to any one of claims 1-10, wherein treatment reduces MRI-PDFF of the patient by at least about 20% compared to baseline.

12. The method according to any one of claims 1-11, wherein at least about one-third of the treated patients achieves a reduction in MRI-PDFF of about 30% compared to baseline.

13. The method according to any one of claims 1-12, wherein said treatment reduces serum levels of a tissue inhibitor of metalloproteinase-1 (TIMP-1) in the patient by at least about 5% as compared to baseline.

14. The method according to any one of claims 1-13, wherein the treatment reduces serum levels of N-terminal procollagen III-peptide (PIII-NP) in the patient by at least about 9% as compared to baseline.

15. The method according to any one of claims 1-14, wherein the plasma triglyceride level of said treated patient does not significantly increase in treatment.

16. The method according to any one of claims 1-15, wherein the treated patient does not experience a grade 3 or 4 triglyceride elevation.

17. the method according to any one of claims 1-16, wherein the PPAR α agonist is a selective PPAR α agonist.

18. the method according to any one of claims 2,3, 5-16, wherein the PPAR α agonist is selected from the group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemofibrate, clinofibrate, bisfibrate, omega-3 fatty acids, GW409544, AZ242, LY518674, NS-220, AVE8134, BMS-711939, argazagliza, mogrosigliza, and sarpogozide.

19. the method according to any one of claims 2,3, 5-16, wherein the PPAR α agonist is selected from the group consisting of aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, pemofibrate, clinofibrate, bisfibrate, omega-3 fatty acids, GW409544, AZ242, LY518674, NS-220, AVE8134, BMS-711939, argazagliza, moggliza, saroglider and elafibranor.

20. the method according to any one of claims 1 to 16, wherein the PPAR α agonist is a fibrate.

21. the method according to any one of claims 1 to 16, wherein the PPAR α agonist is fenofibrate.

22. The method according to any one of claims 1-21, wherein compound 1 is administered.

23. The method according to claim 22, wherein the amount of compound 1 administered is about 20mg once daily.

24. The method according to any one of claims 1-21, wherein compound 2 is administered.

25. A method of treating non-alcoholic steatohepatitis in a non-cirrhosis patient with non-alcoholic steatohepatitis, wherein the method comprises administering to a patient in need thereof once daily about 20mg of compound 1.

26. The method according to claim 25, wherein the patient has grade 1 to 3 fibrosis.

27. The method according to claim 25 or 26, wherein the patient has a magnetic resonance imaging proton density fat fraction (MRI-PDFF) at baseline of at least about 8%.

28. The method according to any one of claims 25-27, wherein the patient has a liver stiffness at baseline of at least about 2.5 kPa.

29. The method of any one of claims 25-28, wherein the patient has a baseline plasma triglyceride level of less than about 250 mg/dL.

30. The method according to any one of claims 25-29, wherein the treatment reduces MRI-PDFF of the patient by at least about 20% compared to baseline.

31. The method according to any one of claims 25-30, wherein at least about one-third of the patients treated with compound 1 achieves a reduction in MRI-PDFF of about 30% compared to baseline.

32. The method according to any one of claims 25-31, wherein said treatment reduces serum levels of a tissue inhibitor of metalloproteinase-1 (TIMP-1) in the patient by at least about 5% as compared to baseline.

33. The method according to any one of claims 25-32, wherein the treatment reduces serum levels of N-terminal procollagen III-peptide (PIII-NP) in the patient by at least about 9% as compared to baseline.

34. The method according to any one of claims 1-33, wherein compound 1 or compound 2 is administered once daily in the evening.

35. A method of treating non-alcoholic steatohepatitis (NASH) in a patient having compensated cirrhosis of the liver due to NASH, wherein the method comprises administering to the patient in need thereof about 20mg of compound 1 once daily.